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| Intellectual disability v11.45 | ANTXR1 | Ida Ertmanska edited their review of gene: ANTXR1: Changed publications to: 38423276, 40962491 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.45 | ANTXR1 |
Ida Ertmanska changed review comment from: PMID: 40962491 Modafferi et al., 2025 Review of 105 GAPO syndrome cases + new case report of a 33yo woman with a homozygous ANTXR1 deletion of exons 4, 5, and 6. PMID: 38423276 Balakrishnan, Goud, & Teegala, 2024 Report of an Indian proband, 3.75yrs old female, with GAPO syndrome. She presented with short stature, dysmorphism, sparse hair growth & lack of appropriate dentition; to: PMID: 40962491 Modafferi et al., 2025 Review of 105 GAPO syndrome cases + new case report of a 33yo woman with a homozygous ANTXR1 deletion of exons 4, 5, and 6. PMID: 38423276 Balakrishnan, Goud, & Teegala, 2024 Report of an Indian proband, 3.75yrs old female, with GAPO syndrome. She presented with short stature, dysmorphism, sparse hair growth & lack of appropriate dentition ANTXR1 association with AR GAPO syndrome is classified as Definitive in ClinGen (Syndromic Disorders GCEP, July 2025). |
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| Intellectual disability v11.45 | ANTXR1 | Ida Ertmanska reviewed gene: ANTXR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38423276; Phenotypes: GAPO syndrome, OMIM:230740, GAPO syndrome, MONDO:0009263, Growth delay-alopecia-pseudoanodontia-optic atrophy syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited polyposis and early onset colorectal cancer - germline testing v4.3 | RNF43 | Terri McVeigh reviewed gene: RNF43: Rating: RED; Mode of pathogenicity: None; Publications: 41002021; Phenotypes: serrated polyposis, colorectal cancer; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.14 | BAG5 |
Matthew Edwards gene: BAG5 was added gene: BAG5 was added to Paediatric or syndromic cardiomyopathy. Sources: NHS GMS,ClinGen Mode of inheritance for gene: BAG5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BAG5 were set to PMID: 35044787; PMID: 37873655; PMID: 38796549 Phenotypes for gene: BAG5 were set to Dilated Cardiomyopathy Review for gene: BAG5 was set to GREEN Added comment: BAG5 curated as moderate-evidence DCM association by ClinGen as of 03/04/2026: https://search.clinicalgenome.org/kb/genes/HGNC:941 with at least 5 homozygous or compound heterozygous early-onset DCM cases. We have detected a homozygous nonsense variant in two affected sibs (with unaffected parents) in our lab via WGS testing. Very sufficient evidence for a green rating for R135 panel Sources: NHS GMS, ClinGen |
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| Dystonia, chorea or related movement disorder, childhood onset v8.19 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Dystonia, chorea or related movement disorder, adult onset v6.11 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Hereditary ataxia, adult onset v9.15 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Intellectual disability v11.45 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Early onset or syndromic epilepsy v9.89 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Likely inborn error of metabolism v9.38 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Paroxysmal central nervous system disorders v4.9 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Ataxia and cerebellar anomalies - childhood onset v9.41 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Intellectual disability v11.45 | PCBP1 |
Aleš Maver gene: PCBP1 was added gene: PCBP1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PCBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PCBP1 were set to 42749777 Phenotypes for gene: PCBP1 were set to Neurodevelopmental disorder with intellectual disability and autism spectrum disorder Penetrance for gene: PCBP1 were set to unknown Review for gene: PCBP1 was set to AMBER Added comment: Deb et al. (2026) identified 16 distinct de novo PCBP1 variants reported as pathogenic in 17 affected individuals from 16 unrelated families. All individuals had intellectual disability, with autism spectrum disorder a prominent feature. Functional studies in primary mouse hippocampal neurons demonstrated impaired dendritic arborization associated with PCBP1 variants. RNA sequencing of patient-derived T cells identified a distinctive splicing signature with increased exon skipping, supporting disruption of PCBP1-mediated splicing regulation. The human genetic and functional evidence supports a monoallelic PCBP1-related neurodevelopmental disorder. Sources: Literature |
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| Dilated and arrhythmogenic cardiomyopathy v4.11 | CD36 |
Oliver Watkinson gene: CD36 was added gene: CD36 was added to Dilated and arrhythmogenic cardiomyopathy. Sources: Other Mode of inheritance for gene: CD36 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: CD36 were set to PMID 41174181; 42895716 Phenotypes for gene: CD36 were set to Dilated cardiomyopathy Penetrance for gene: CD36 were set to Incomplete Review for gene: CD36 was set to AMBER Added comment: There are now a couple of major publications (listed) using demonstrating that a relatively common variant in this gene (Y325*) is responsible for quite a large burden of dilated cardiomyopathy in patients of African ancestry, particularly in homozygous state. I'm not sure (yet) how we would handle this variant in terms of cascade testing, but I think it might be helpful diagnostically for this variant to be included on this panel. Sources: Other |
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| Intellectual disability v11.45 | EMG1 | Ida Ertmanska Tag founder-effect tag was added to gene: EMG1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tubulointerstitial kidney disease v3.35 | FAN1 |
Aakash Joshi gene: FAN1 was added gene: FAN1 was added to Tubulointerstitial kidney disease. Sources: Literature Mode of inheritance for gene: FAN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAN1 were set to PMCID 11920115; PMID 22772369 Phenotypes for gene: FAN1 were set to Interstitial fibrosis; chronic renal failure; tubulointerstitial nephritis Penetrance for gene: FAN1 were set to Complete Review for gene: FAN1 was set to GREEN Added comment: Biallelic variants in FAN1 have been established to be associated with a condition known as Karyomegalic tubulointerstitial nephritis (KMIN, OMIM #614817). A paper by Zhou (PMID 22772369) identified that 9 families with the KMIN had biallelic variants in FAN1. A more recent paper (PMCID 11920115) showed a further individual with KMIN had a panel which then identified a homozygous FAN1 variant. This gene is currently only on the Unexplained kidney failure in the young panel, but given the specific phenotype of progressive chronic interstitial nephritis it should be included in this panel. Sources: Literature |
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| Respiratory ciliopathies including non-CF bronchiectasis v5.4 | ARMC2 |
Aakash Joshi gene: ARMC2 was added gene: ARMC2 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature Mode of inheritance for gene: ARMC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARMC2 were set to PMCID 11954227 Phenotypes for gene: ARMC2 were set to recurrent respiratory infections; bronchitis; rhinosinusitis; sperm abnormalities Penetrance for gene: ARMC2 were set to unknown Review for gene: ARMC2 was set to RED Added comment: PMCID 11954227 identified one individual with a homozygous in ARMC2 which resulted in the known sperm abnormalities, but in addition to this was found to have Primary Ciliary Dyskinesia features with recurrent respiratory infections, bronchitis and rhinosinusitis. Sources: Literature |
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| Renal ciliopathies v5.2 | TULP3 |
Aakash Joshi gene: TULP3 was added gene: TULP3 was added to Renal ciliopathies. Sources: Literature Mode of inheritance for gene: TULP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TULP3 were set to PMCID 11742108; PMCID 12432116 Phenotypes for gene: TULP3 were set to renal cysts; renal ciliopathy Penetrance for gene: TULP3 were set to Complete Review for gene: TULP3 was set to GREEN Added comment: TULP3 is known to cause a renal cystic disease phenotype but recent literature has identified that it is associated with transporting integral membrane and membrane-associated lipidated proteins into the cilia (PMCID 11742108 and PMCID 12432116). It would therefore fit with a renal ciliopathy and is also known to cause liver fibrosis and some evidence to suggest it has been associated with skeletal features (PMCID 12432116). Sources: Literature |
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| Pituitary hormone deficiency v4.13 | FGF8 | Ida Ertmanska Publications for gene: FGF8 were set to 22319038; 21832120; 20463092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.6 | FGF8 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 HPE families is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at least 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 HPE families is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. A watchlist_moi tag was added. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.12 | FGF8 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at least 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at least 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. A watchlist_moi tag was added. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.6 | FGF8 | Ida Ertmanska Phenotypes for gene: FGF8 were changed from Holoprosencephaly to hypogonadotropic hypogonadism 6 with or without anosmia, MONDO:0012988; Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.5 | FGF8 | Ida Ertmanska Publications for gene: FGF8 were set to 27363716 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska Tag watchlist_moi tag was added to gene: FGF8. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.12 | FGF8 | Ida Ertmanska Tag watchlist_moi tag was added to gene: FGF8. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.12 | FGF8 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at least 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.17 | COMMD4 |
Alexandra Njegic gene: COMMD4 was added gene: COMMD4 was added to Paediatric disorders - additional genes. Sources: Literature Mode of inheritance for gene: COMMD4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COMMD4 were set to 40601774; 39937864 Phenotypes for gene: COMMD4 were set to Ritscher-Schinzel Syndrome Penetrance for gene: COMMD4 were set to unknown Mode of pathogenicity for gene: COMMD4 was set to Other Review for gene: COMMD4 was set to AMBER Added comment: PMID: 40601774 identified a homozygous missense variant in COMMD4 (p.Leu41Arg (L41R)) which was shown in vitro to decrease the steady-state abundance of COMMD4 when compared with the parental cells (shown with western blot analysis on HEK 293T cells carrying a-L41R knock-in, probands deceased and therefore no patient-derived sample available); knock-in cells also displayed reduced cell surface abundance of ITGB1 and LRP1 vs. wild-type cells in Western blotting, suggesting a defect in Commander-mediated cargo recycling. Article also ID variants in COMMD9 and CCDC93 to conclude that RSS is a recyclinopathy due to dysfunctional SNX17/Commander/WASH-mediated endosome recycling. Also as reported in DET1 submission, these proband were also homozygous for a variant in DET1 (c.76C>T, p.R26W). Sources: Literature |
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| Fetal anomalies v8.17 | BHLHE22 | Ida Ertmanska Tag watchlist was removed from gene: BHLHE22. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.14 | BHLHE22 | Ida Ertmanska Publications for gene: BHLHE22 were set to 39502664 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.13 | BHLHE22 | Ida Ertmanska commented on gene: BHLHE22 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.13 | BHLHE22 |
Ida Ertmanska Tag watchlist was removed from gene: BHLHE22. Tag Q4_26_promote_green tag was added to gene: BHLHE22. |
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| Intellectual disability v11.45 | BHLHE22 | Ida Ertmanska Publications for gene: BHLHE22 were set to 39502664 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.44 | BHLHE22 |
Ida Ertmanska Tag watchlist was removed from gene: BHLHE22. Tag Q4_26_promote_green tag was added to gene: BHLHE22. |
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| Intellectual disability v11.44 | BHLHE22 | Ida Ertmanska commented on gene: BHLHE22 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.44 | NCKAP1 | John Taylor reviewed gene: NCKAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33157009, 40551827, 41462819; Phenotypes: cognitive impairment, ID, ADHD, anxiety, depression; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.12 | FGF8 | Achchuthan Shanmugasundram Phenotypes for gene: FGF8 were changed from Hypogonadotropic hypogonadism 6 with or without anosmia (612702) to Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702; hypogonadotropic hypogonadism 6 with or without anosmia, MONDO:0012988 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.7 | FGF8 | Achchuthan Shanmugasundram Phenotypes for gene: FGF8 were changed from hypogonadotropic hypogonadism 6 with or without anosmia, MONDO:0012988; Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702 to Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702; hypogonadotropic hypogonadism 6 with or without anosmia, MONDO:0012988 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.40 | ACBD6 | Eleanor Williams Phenotypes for gene: ACBD6 were changed from Neurodevelopmental disorder with progressive movement abnormalities, OMIM:620785 to Neurodevelopmental disorder with progressive movement abnormalities, OMIM:620785; neurodevelopmental disorder with progressive movement abnormalities, MONDO:0968976 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.39 | BLM | Eleanor Williams Phenotypes for gene: BLM were changed from Bloom syndrome, OMIM:210900; Microcephalic primordial dwarfism to Bloom syndrome, OMIM:210900; Bloom syndrome, MONDO:0008876; Microcephalic primordial dwarfism | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.38 | ATRX | Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotypes last accessed on 14th Oct 2026 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.38 | ATRX | Eleanor Williams Phenotypes for gene: ATRX were changed from Mental retardation-hypotonic facies syndrome, X-linked, 309580 (Microcephaly); Alpha-thalassemia/mental retardation syndrome, 301040 (Microcephaly) to Intellectual disability-hypotonic facies syndrome, X-linked, OMIM:309580; intellectual disability-hypotonic facies syndrome, X-linked, 1, MONDO:0010663; Alpha-thalassemia/impaired intellectual development syndrome, OMIM:301040; alpha thalassemia-X-linked intellectual disability syndrome, MONDO:0010519 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.89 | SHROOM4 | Ida Ertmanska edited their review of gene: SHROOM4: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.44 | UROC1 | Ida Ertmanska changed review comment from: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability.; to: Comment on list classification: There are 5 individuals from 4 families reported in literature with biallelic variants in UROC1 and urocanic aciduria. 2/5 individuals with Urocanase deficiency were asymptomatic, 2/5 presented with intellectual disability (1 mild, 1 not specified), and 1 individual was noted to have a non-specific 'neurologic' phenotype. In addition, PMID: 30619714 and PMID: 32439973 state that the biochemical phenotype of Urocanase deficiency is benign. In 2/4 studies, only UROC1 targeted sequencing was performed. As there is conflicting evidence for this gene-disease association, UROC1 should be downgraded to Red for Intellectual disability. An expert-review tag was added to ensure GMS agreement on this demotion from Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.44 | UROC1 | Ida Ertmanska Tag Q4_25_expert_review tag was added to gene: UROC1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.17 | TSEN34 | Ida Ertmanska Tag Q4_25_expert_review tag was added to gene: TSEN34. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.17 | TSEN34 | Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. The phenotype is fetally relevant as PCH can be detected on antenatal scans (PMID: 38165124). While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.44 | TSEN34 | Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Intellectual disability until more evidence emerges. Expert review will be sought for this demotion from Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.44 | TSEN34 | Ida Ertmanska Tag Q4_25_expert_review tag was added to gene: TSEN34. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.41 | TSEN34 | Ida Ertmanska changed review comment from: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges.; to: Comment on list classification: There is one patient reported in literature with a biallelic variant in TSEN34 and Pontocerebellar hypoplasia type 2. While TSEN34 shares a biochemical function with other genes known to cause Pontocerebellar hypoplasia type 2, the clinical evidence for this gene-disease association is lacking in literature. Hence, TSEN34 should be demoted to Amber for Ataxia and cerebellar anomalies - narrow panel, until more evidence emerges. Expert review will be sought for this demotion from Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.41 | TSEN34 | Ida Ertmanska Tag Q4_25_expert_review tag was added to gene: TSEN34. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.38 | SMN1 | Eleanor Williams commented on gene: SMN1: Removed the Q2_26_demote_red tag as this gene will be discussed separately from the usual panel update process with NHSE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.38 | SMN1 |
Eleanor Williams Tag Q2_26_demote_red was removed from gene: SMN1. Tag Q2_26_expert_review was removed from gene: SMN1. |
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| Paediatric motor neuronopathies v3.20 | SMN1 | Eleanor Williams commented on gene: SMN1: Removed the Q2_26_demote_red tag as this gene will be discussed separately from the usual panel update process with NHSE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.20 | SMN1 |
Eleanor Williams Tag Q2_26_demote_red was removed from gene: SMN1. Tag Q2_26_expert_review was removed from gene: SMN1. |
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| Arthrogryposis v10.23 | SMN1 | Eleanor Williams commented on gene: SMN1: Removed the Q2_26_demote_red tag as this gene will be discussed separately from the usual panel update process with NHSE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.23 | SMN1 |
Eleanor Williams Tag Q2_26_demote_red was removed from gene: SMN1. Tag Q2_26_expert_review was removed from gene: SMN1. |
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| Monogenic hearing loss v6.51 | POLR1D | Ida Ertmanska Mode of inheritance for gene: POLR1D was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.50 | POLR1D | Ida Ertmanska edited their review of gene: POLR1D: Changed publications to: 24603435, 25790162, 27448281, 36158048, 39289962, 41752027, 42706666 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.50 | POLR1D |
Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 36158048 Yang, Zhen, & Li., 2022 Case report - Chinese fetus with micrognathia and a het POLR1D NM_015972:c.91del, p.Q31Rfs*10 variant, inherited from a healthy mother. Method: Trio WES. After abortion at 20 weeks, fetus showed "characteristic facial dysmorphism with retrognathia, downward-slanting palpebral fissures, lower eyelid colobomas between the external and middle thirds, low-set microtic ears, and cleft palate without cleft lip." PMID: 39289962 Sun et al. ,2024 Report of a Chinese female, 8 years old, with Treacher Collins Syndrome 2 (conductive hearing loss, smaller jaw, bilateral preauricular fistulas and cup-shaped ear deformities). She was het for POLR1D NM_015972.4:c.38_47del variant, inherited from the mother (mildly affected, small jaw noted). PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. FUNCTIONAL: PMID: 27448281 - Watt et al., 2016 - zebrafish Polr1c-/- and polr1d-/- mutant embryos had smaller eyes than WT fish, disrupted midbrain-hindbrain boundary and necrotic cranial tissue at 24 hpf. At 3 dpf, polr1c-/- and polr1d-/- mutants showed smaller heads, microphthalmia, and hyploplastic jaws. Alcian blue staining revealed cartilage is hypoplastic in the knockout fish. POLR1D is associated with AD, AR Treacher Collins syndrome 2, MIM:613717 (OMIM accessed 12th Oct 2026). The assocation between AD Treacher Collins syndrome 2 and POLR1D was classified as Definitive in ClinGen (12/15/2022, Craniofacial Malformations GCEP).; to: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 36158048 Yang, Zhen, & Li., 2022 Case report - Chinese fetus with micrognathia and a het POLR1D NM_015972:c.91del, p.Q31Rfs*10 variant, inherited from a healthy mother. Method: Trio WES. After abortion at 20 weeks, fetus showed "characteristic facial dysmorphism with retrognathia, downward-slanting palpebral fissures, lower eyelid colobomas between the external and middle thirds, low-set microtic ears, and cleft palate without cleft lip." PMID: 39289962 Sun et al. ,2024 Report of a Chinese female, 8 years old, with Treacher Collins Syndrome 2 (conductive hearing loss, smaller jaw, bilateral preauricular fistulas and cup-shaped ear deformities). She was het for POLR1D NM_015972.4:c.38_47del variant, inherited from the mother (mildly affected, small jaw noted). PMID: 41752027 Camarillo-Benitez et al., 2026 Report of 11 patients from 3 Mexican families. Seq method: WES + Sanger. F1 and F2 probands harboured TCOF1 variants. In Family 3, a heterozygous pathogenic POLR1D variant, c.290_291delAG (p.G99fs), was identified among multiple affected relatives (5 females). 3/5 affected individuals had severe hearing loss. PMID: 42706666 Nevondwe et al., 2026 Report of 10 South African probands with Treacher Collins Syndrome, including individual FRASC28 (7yo male) with a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. FUNCTIONAL: PMID: 27448281 - Watt et al., 2016 - zebrafish Polr1c-/- and polr1d-/- mutant embryos had smaller eyes than WT fish, disrupted midbrain-hindbrain boundary and necrotic cranial tissue at 24 hpf. At 3 dpf, polr1c-/- and polr1d-/- mutants showed smaller heads, microphthalmia, and hyploplastic jaws. Alcian blue staining revealed cartilage is hypoplastic in the knockout fish. POLR1D is associated with AD, AR Treacher Collins syndrome 2, MIM:613717 (OMIM accessed 12th Oct 2026). The assocation between AD Treacher Collins syndrome 2 and POLR1D was classified as Definitive in ClinGen (12/15/2022, Craniofacial Malformations GCEP). |
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| Monogenic hearing loss v6.50 | POLR1D | Ida Ertmanska Phenotypes for gene: POLR1D were changed from to Treacher Collins syndrome 2, OMIM:613717; Treacher Collins syndrome 2, MONDO:0013385 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.49 | POLR1D | Ida Ertmanska Publications for gene: POLR1D were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.48 | POLR1D | Ida Ertmanska Classified gene: POLR1D as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.48 | POLR1D | Ida Ertmanska Gene: polr1d has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.47 | POLR1D |
Ida Ertmanska Tag Q3_26_promote_green was removed from gene: POLR1D. Tag Q4_26_promote_green tag was added to gene: POLR1D. |
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| Monogenic hearing loss v6.47 | POLR1D | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: POLR1D. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.47 | POLR1D |
Ida Ertmanska changed review comment from: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). All 3 biallelic individuals were noted to have hearing loss. Numerous other individuals with TCS2 have heterozygous POLR1D variants. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. ; to: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). All 3 biallelic individuals were noted to have hearing loss. Numerous other individuals with TCS2 have heterozygous POLR1D variants. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. |
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| Monogenic hearing loss v6.47 | POLR1D |
Ida Ertmanska changed review comment from: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). All 3 biallelic individuals were noted to have hearing loss. Numerous other individuals with TCS2 have heterozygous POLR1D variants. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. ; to: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). All 3 biallelic individuals were noted to have hearing loss. Numerous other individuals with TCS2 have heterozygous POLR1D variants. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. |
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| Monogenic hearing loss v6.47 | POLR1D |
Ida Ertmanska changed review comment from: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). Numerous other individuals with TCS2 have heterozygous POLR1D variants. All 3 biallelic individuals were noted to have hearing loss. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. ; to: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). All 3 biallelic individuals were noted to have hearing loss. Numerous other individuals with TCS2 have heterozygous POLR1D variants. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. |
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| Monogenic hearing loss v6.47 | POLR1D |
Ida Ertmanska changed review comment from: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). Numerous other individuals with TCS2 have heterozygous POLR1D variants. All 3 biallelic individuals were noted to have hearing loss. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss.; to: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). Numerous other individuals with TCS2 have heterozygous POLR1D variants. All 3 biallelic individuals were noted to have hearing loss. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. |
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| Monogenic hearing loss v6.47 | POLR1D | Ida Ertmanska commented on gene: POLR1D: Comment on list classification: There are 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). Numerous other individuals with TCS2 have heterozygous POLR1D variants. All 3 biallelic individuals were noted to have hearing loss. As per GeneReviews entry for TCS, conductive hearing loss is one of the main features of this syndrome, present in >75% of individuals (https://www.ncbi.nlm.nih.gov/sites/books/NBK1532/). Hence, this gene should be rated Green on Monogenic hearing loss. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.47 | POLR1D | Ida Ertmanska edited their review of gene: POLR1D: Changed publications to: 24603435, 25790162, 27448281, 36158048, 39289962, 42706666 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.47 | POLR1D |
Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. FUNCTIONAL: PMID: 27448281 - Watt et al., 2016 - zebrafish Polr1c-/- and polr1d-/- mutant embryos had smaller eyes than WT fish, disrupted midbrain-hindbrain boundary and necrotic cranial tissue at 24 hpf. At 3 dpf, polr1c-/- and polr1d-/- mutants showed smaller heads, microphthalmia, and hyploplastic jaws. Alcian blue staining revealed cartilage is hypoplastic in the knockout fish. POLR1D is associated with AD, AR Treacher Collins syndrome 2, MIM:613717 (OMIM accessed 12th Oct 2026). The assocation between AD Treacher Collins syndrome 2 and POLR1D was classified as Definitive in ClinGen (12/15/2022, Craniofacial Malformations GCEP).; to: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 36158048 Yang, Zhen, & Li., 2022 Case report - Chinese fetus with micrognathia and a het POLR1D NM_015972:c.91del, p.Q31Rfs*10 variant, inherited from a healthy mother. Method: Trio WES. After abortion at 20 weeks, fetus showed "characteristic facial dysmorphism with retrognathia, downward-slanting palpebral fissures, lower eyelid colobomas between the external and middle thirds, low-set microtic ears, and cleft palate without cleft lip." PMID: 39289962 Sun et al. ,2024 Report of a Chinese female, 8 years old, with Treacher Collins Syndrome 2 (conductive hearing loss, smaller jaw, bilateral preauricular fistulas and cup-shaped ear deformities). She was het for POLR1D NM_015972.4:c.38_47del variant, inherited from the mother (mildly affected, small jaw noted). PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. FUNCTIONAL: PMID: 27448281 - Watt et al., 2016 - zebrafish Polr1c-/- and polr1d-/- mutant embryos had smaller eyes than WT fish, disrupted midbrain-hindbrain boundary and necrotic cranial tissue at 24 hpf. At 3 dpf, polr1c-/- and polr1d-/- mutants showed smaller heads, microphthalmia, and hyploplastic jaws. Alcian blue staining revealed cartilage is hypoplastic in the knockout fish. POLR1D is associated with AD, AR Treacher Collins syndrome 2, MIM:613717 (OMIM accessed 12th Oct 2026). The assocation between AD Treacher Collins syndrome 2 and POLR1D was classified as Definitive in ClinGen (12/15/2022, Craniofacial Malformations GCEP). |
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| Monogenic hearing loss v6.47 | POLR1D | Ida Ertmanska reviewed gene: POLR1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 24603435, 25790162, 27448281, 42706666; Phenotypes: Treacher Collins syndrome 2, OMIM:613717, Treacher Collins syndrome 2, MONDO:0013385; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.19 | POLR1D | Ida Ertmanska Phenotypes for gene: POLR1D were changed from Treacher Collins syndrome 2 613717 to Treacher Collins syndrome 2, OMIM:613717; Treacher Collins syndrome 2, MONDO:0013385 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.18 | POLR1D | Ida Ertmanska Publications for gene: POLR1D were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.17 | POLR1D | Ida Ertmanska edited their review of gene: POLR1D: Changed publications to: 24603435, 25790162, 27448281, 42706666 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.13 | POLR1D | Ida Ertmanska Phenotypes for gene: POLR1D were changed from Treacher Collins syndrome 2, OMIM:613717 to Treacher Collins syndrome 2, OMIM:613717; Treacher Collins syndrome 2, MONDO:0013385 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.12 | POLR1D | Ida Ertmanska Publications for gene: POLR1D were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.11 | POLR1D | Ida Ertmanska edited their review of gene: POLR1D: Changed publications to: 24603435, 25790162, 27448281, 42706666 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.11 | POLR1D | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: POLR1D. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.17 | POLR1D | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are now 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). The majority of individuals with TCS2 have heterozygous POLR1D variants. The 3 biallelic individuals were noted to have craniofacial malformations including mandibular hypoplasia and micro/retrognathia. Hence, the MOI should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are now 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). The majority of individuals with TCS2 have heterozygous POLR1D variants. The 3 biallelic individuals were noted to have craniofacial malformations including mandibular hypoplasia and micro/retrognathia. This gene-phenotype assocation is supported by a knockout zebrafish model. Hence, the MOI should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.17 | POLR1D | Ida Ertmanska commented on gene: POLR1D: Comment on mode of inheritance: There are now 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). The majority of individuals with TCS2 have heterozygous POLR1D variants. The 3 biallelic individuals were noted to have craniofacial malformations including mandibular hypoplasia and micro/retrognathia. Hence, the MOI should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.11 | POLR1D | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are now 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). The majority of individuals with TCS2 have heterozygous POLR1D variants. Also, the biallelic individuals were noted to have craniofacial malformations but no clefting. Hence, the MOI should be updated to MONOALLELIC.; to: Comment on mode of inheritance: There are now 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). The majority of individuals with TCS2 have heterozygous POLR1D variants. Also, the biallelic individuals were noted to have craniofacial malformations but no clefting. Hence, the MOI should be updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.11 | POLR1D | Ida Ertmanska edited their review of gene: POLR1D: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.11 | POLR1D | Ida Ertmanska commented on gene: POLR1D: Comment on mode of inheritance: There are now 3 probands reported in literature with biallelic POLR1D variants and Treacher Collins Syndrome 2 (TCS2). The majority of individuals with TCS2 have heterozygous POLR1D variants. Also, the biallelic individuals were noted to have craniofacial malformations but no clefting. Hence, the MOI should be updated to MONOALLELIC. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.17 | POLR1D |
Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands (P96) was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. HOWEVER Suppl Table S1 lists this proband as 'previously reported' - most likely overlapping a proband from PMID: 24603435. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes.; to: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. FUNCTIONAL: PMID: 27448281 - Watt et al., 2016 - zebrafish Polr1c-/- and polr1d-/- mutant embryos had smaller eyes than WT fish, disrupted midbrain-hindbrain boundary and necrotic cranial tissue at 24 hpf. At 3 dpf, polr1c-/- and polr1d-/- mutants showed smaller heads, microphthalmia, and hyploplastic jaws. Alcian blue staining revealed cartilage is hypoplastic in the knockout fish. POLR1D is associated with AD, AR Treacher Collins syndrome 2, MIM:613717 (OMIM accessed 12th Oct 2026). The assocation between AD Treacher Collins syndrome 2 and POLR1D was classified as Definitive in ClinGen (12/15/2022, Craniofacial Malformations GCEP). |
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| Clefting v7.11 | POLR1D |
Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes.; to: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. FUNCTIONAL: PMID: 27448281 - Watt et al., 2016 - zebrafish Polr1c-/- and polr1d-/- mutant embryos had smaller eyes than WT fish, disrupted midbrain-hindbrain boundary and necrotic cranial tissue at 24 hpf. At 3 dpf, polr1c-/- and polr1d-/- mutants showed smaller heads, microphthalmia, and hyploplastic jaws. Alcian blue staining revealed cartilage is hypoplastic in the knockout fish. POLR1D is associated with AD, AR Treacher Collins syndrome 2, MIM:613717 (OMIM accessed 12th Oct 2026). The assocation between AD Treacher Collins syndrome 2 and POLR1D was classified as Definitive in ClinGen (12/15/2022, Craniofacial Malformations GCEP). |
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| Skeletal dysplasia v10.17 | POLR1D |
Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes.; to: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands (P96) was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. HOWEVER Suppl Table S1 lists this proband as 'previously reported' - most likely overlapping a proband from PMID: 24603435. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. |
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| Clefting v7.11 | POLR1D | Ida Ertmanska reviewed gene: POLR1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 24603435, 25790162, 42706666; Phenotypes: Treacher Collins syndrome 2, OMIM:613717, Treacher Collins syndrome 2, MONDO:0013385; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.17 | POLR1D |
Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014 Proband hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes.; to: PMID: 24603435 Schaefer et al., 2014 Report of 2 families. Seq method: direct sequencing of TCOF1, POLR1D, and POLR1C. F1 - proband is a young girl born to distant cousins from Turkey; she had hearing loss, microretrognathia, malar hypoplasia, right-ear dysplasia, and downslanting palpebral fissures. Normal motor and cognitive development. She was hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. Parents and sister were unaffected and het for the same variant. F2 - 3 affected children hom for POLR1D c.163C>G, p.Leu55Val variant, born to first cousin parents from Turkey (same region as F1). Phenotype: hearing loss, malar hypoplasia, retrognathism. Parents were het for p.Leu55Val and unaffected. Haplotype analysis revealed both families had different microsatellite markers around POLR1D - evidence against a founder mutation. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. |
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| Skeletal dysplasia v10.17 | POLR1D |
Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014 Proband hom for POLR1D c.163C>G, p.Leu55Val variant. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p. Gly88AlafsTer13). He presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes.; to: PMID: 24603435 Schaefer et al., 2014 Proband hom for POLR1D c.163C>G, p.Leu55Val variant - 2 alleles reported in gnomAD v4.1.2, no hmz. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p.Gly88AlafsTer13). Variant not present in gnomAD 4.1.2. Individual presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. |
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| Skeletal dysplasia v10.17 | POLR1D |
Ida Ertmanska changed review comment from: PMID: 24603435 Schaefer et al., 2014 Proband hom for POLR1D c.163C>G, p.Leu55Val variant. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p. Gly88AlafsTer13). He presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes.; to: PMID: 24603435 Schaefer et al., 2014 Proband hom for POLR1D c.163C>G, p.Leu55Val variant. PMID: 25790162 Vincent et al., 2015 Cohort of 146 patients with Treacher Collins Syndrome, mostly of French ancestry. 92 patients had a variant in TCOF1, 9 in POLR1D, and none in POLR1C. All patients with POLR1D presented with mandibular hypoplasia (7/7) and deafness (5/5 assessed), but not with microcephaly, cardiac or renal malformations, anomaly of the limbs, or choanal atresia. One of the probands was homozygous for the c.163C>G, p.Leu55Val variant in POLR1D. Seq method: non-NGS sequencing of TCOF1, POLR1D, POLR1C, and EFTUD2 using Sanger seq, arrays, liquid chromatography. PMID: 42706666 Nevondwe et al., 2026 Report of a South African proband (FRASC28, 7yo male) with Treacher Collins Syndrome and a homozygous POLR1D variant NM_015972.4:c.261delA, (p. Gly88AlafsTer13). He presented with malar flattening, mandibular hypoplasia, low‐set ears, ear tags, hearing loss, undescended testes. Parental segregation analysis was not performed, but apparently they were unaffected. Seq method: custom NGS gene panel including TCOF1, POLR1C, and POLR1D genes. |
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| Skeletal dysplasia v10.17 | POLR1D | Ida Ertmanska reviewed gene: POLR1D: Rating: GREEN; Mode of pathogenicity: None; Publications: 24603435, 25790162, 42706666; Phenotypes: Treacher Collins syndrome 2, OMIM:613717, Treacher Collins syndrome 2, MONDO:0013385; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.19 | KIT | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: KIT. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.19 | KIT | Ida Ertmanska Phenotypes for gene: KIT were changed from Mastocytosis, cutaneous, OMIM:154800; Piebaldism, OMIM:172800 to Mastocytosis, cutaneous, OMIM:154800; Piebaldism, OMIM:172800; piebaldism, MONDO:0008244 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.47 | KIT | Ida Ertmanska Phenotypes for gene: KIT were changed from Piebaldism and congenital sensorineural hearing loss to Piebaldism, OMIM:172800; piebaldism, MONDO:0008244; hearing loss disorder, MONDO:0005365 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.46 | KIT | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: KIT. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.46 | KIT | Ida Ertmanska edited their review of gene: KIT: Changed phenotypes to: Piebaldism, OMIM:172800, piebaldism, MONDO:0008244, hearing loss disorder, MONDO:0005365 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.46 | KIT | Ida Ertmanska reviewed gene: KIT: Rating: GREEN; Mode of pathogenicity: None; Publications: 23399981; Phenotypes: Piebaldism, OMIM:172800, piebaldism, MONDO:0008244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.18 | KIT | Ida Ertmanska reviewed gene: KIT: Rating: GREEN; Mode of pathogenicity: None; Publications: 23399981; Phenotypes: Piebaldism, OMIM:172800, piebaldism, MONDO:0008244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.14 | LAMB1 | Ida Ertmanska Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, OMIM:615191; cobblestone lissencephaly without muscular or ocular involvement, MONDO:0014077 to Leukoencephalopathy without lacunae, adult-onset, OMIM:621424; leukoencephalopathy without lacunae, adult-onset, MONDO:0980752; Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.13 | LAMB1 | Ida Ertmanska Publications for gene: LAMB1 were set to 32548278; 34606115; 23472759; 25925986; 29888467 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.12 | LAMB1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: LAMB1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.12 | LAMB1 | Ida Ertmanska commented on gene: LAMB1: Comment on mode of inheritance: There are multiple patients reported with heterozygous frameshift LAMB1 variants and an adult-onset cerebral small vessel disease with leukoencephalopathy. There is only one individual reported to date with a biallelic missense variant and an adult-onset neurodegenerative disorder (PMID: 32548278). Hence, the mode of inheritance of this gene should be changed to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' only. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.27 | LAMB1 | Ida Ertmanska Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, OMIM:615191; cobblestone lissencephaly without muscular or ocular involvement, MONDO:0014077 to Leukoencephalopathy without lacunae, adult-onset, OMIM:621424; leukoencephalopathy without lacunae, adult-onset, MONDO:0980752; Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.26 | LAMB1 | Ida Ertmanska Publications for gene: LAMB1 were set to 32548278; 34606115; 23472759; 25925986; 29888467 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.25 | LAMB1 |
Ida Ertmanska Tag Q4_26_expert_review tag was added to gene: LAMB1. Tag Q4_26_MOI tag was added to gene: LAMB1. |
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| Leukodystrophy, adult onset v7.12 | LAMB1 | Ida Ertmanska reviewed gene: LAMB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32548278, 34606115, 37063705, 39082428; Phenotypes: Leukoencephalopathy without lacunae, adult-onset, OMIM:621424, leukoencephalopathy without lacunae, adult-onset, MONDO:0980752, Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.25 | LAMB1 | Ida Ertmanska commented on gene: LAMB1: Comment on mode of inheritance: There are multiple patients reported with heterozygous frameshift LAMB1 variants and an adult-onset cerebral small vessel disease with leukoencephalopathy. There is only one individual reported to date with a biallelic missense variant and an adult-onset neurodegenerative disorder (PMID: 32548278). Hence, the mode of inheritance of this gene should be changed to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', with expert review to ensure GMS agreement on this MOI 'demotion'. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.25 | LAMB1 | Ida Ertmanska edited their review of gene: LAMB1: Changed publications to: 32548278, 34606115, 37063705, 39082428 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.25 | LAMB1 |
Ida Ertmanska changed review comment from: PMID: 32548278 Yasuda et al., 2020 Report of a 37-year-old Japanese woman with headache, memory loss, mild flexion of retinal vessels, and gait disturbance. She was born to consanguineous parents. Her symptoms started at 22 yrs with a migraine. Brain MRI showed a cerebral white matter lesion at age 30 years. Wechsler Adult Intelligence Scale–Third Edition indicated a full-scale IQ of 69 - borderline ID. Seq method: targeted exome seq of 115 genes. She was found to be homozygous for LAMB1: c.1378T>C, p.Cys460Arg variant. Parents confirmed het. There is only 1 het individual reported in gnomAD v4.1.2 with this variant. Authors pose that "the effect of missense mutations on the phenotype may be milder compared with that of frameshift mutations." Functional support: PMID: 40237576 Yasuda et al., 2025 - Drosophila melanogaster model. Study found that the LAMB1 fly ortholog LanB1 gene is expressed on the surface of adult fly brains in a subset of glia cells. While human LAMB1 was not able to function in flies, in vivo overexpression and rescue experiments using analogous variants in fly LanB1 suggested that the frameshift variants behave as strong LoF alleles whereas a missense variant functions as a milder LoF allele. LAMB1 is associated with AD Leukoencephalopathy without lacunae, adult-onset, OMIM:621424 & AR Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191 (OMIM accessed 9th Oct 2026).; to: PMID: 32548278 Yasuda et al., 2020 - BIALLELIC ADULT CASE Report of a 37-year-old Japanese woman with headache, memory loss, mild flexion of retinal vessels, and gait disturbance. She was born to consanguineous parents. Her symptoms started at 22 yrs with a migraine. Brain MRI showed a cerebral white matter lesion at age 30 years. Wechsler Adult Intelligence Scale–Third Edition indicated a full-scale IQ of 69 - borderline ID. Seq method: targeted exome seq of 115 genes. She was found to be homozygous for LAMB1: c.1378T>C, p.Cys460Arg variant. Parents confirmed het. There is only 1 het individual reported in gnomAD v4.1.2 with this variant. Authors pose that "the effect of missense mutations on the phenotype may be milder compared with that of frameshift mutations." Functional support: PMID: 40237576 Yasuda et al., 2025 - Drosophila melanogaster model. Study found that the LAMB1 fly ortholog LanB1 gene is expressed on the surface of adult fly brains in a subset of glia cells. While human LAMB1 was not able to function in flies, in vivo overexpression and rescue experiments using analogous variants in fly LanB1 suggested that the frameshift variants behave as strong LoF alleles whereas a missense variant functions as a milder LoF allele. MONOALLELIC ADULT CASES: PMID: 34606115 Aloui et al., 2021 - exome data of 258 cerebral small vessel disease patients. 4 patients had het frameshift variants in LAMB1 residues 1721-1750 - predicted to escape NMD (plus P5 with a het splice variant but not much detail provided). Age at first symptom was 20-67 yrs for patients 1-4. Common phenotype was hippocampal memory defect and leukoencephalopathy. PMID: 37063705 Morel et al., 2023 - report of 6 patients from 2 unrelated families with het end-truncating LAMB1 variations escaping NMD. Method: targeted seq of 8 cerebral small vessel disease genes. Patients were 30-80 yo at examination. The 4 patients older than 50 years presented with an amnestic syndrome of the hippocampal type (ASHT) with mild executive dysfunction and diffuse leukoencephalopathy. Significant cognitive complaints were also present in the 2 younger patients. PMID: 39082428 Cho et al., 2024 - Cohort of 257 suspected Cerebral Small-Vessel Disease cases. P11 had a het LAMB1 variant p.Leu1730Ter. She had memory deficit and migraine with aura when she was recruited. She had transient ischemic attack at the age of 57 years, stroke at the age of 61 years, and passed away at the age of 67 years. Brain MRI taken at the age of 64 years showed extensive confluent white matter hyperintensities, and lacunar infarcts LAMB1 is associated with AD Leukoencephalopathy without lacunae, adult-onset, OMIM:621424 & AR Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191 (OMIM accessed 9th Oct 2026). |
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| Neurodegenerative disorders, adult onset v9.25 | LAMB1 |
Ida Ertmanska changed review comment from: PMID: 32548278 Yasuda et al., 2020 Report of a 37-year-old Japanese woman with headache, memory loss, mild flexion of retinal vessels, and gait disturbance. She was born to consanguineous parents. Her symptoms started at 22 yrs with a migraine. Brain MRI showed a cerebral white matter lesion at age 30 years. Wechsler Adult Intelligence Scale–Third Edition indicated a full-scale IQ of 69 - borderline ID. Seq method: targeted exome seq of 115 genes. She was found to be homozygous for LAMB1: c.1378T>C, p.Cys460Arg variant. Parents confirmed het. There is only 1 het individual reported in gnomAD v4.1.2 with this variant. Authors pose that "the effect of missense mutations on the phenotype may be milder compared with that of frameshift mutations." LAMB1 is associated with AD Leukoencephalopathy without lacunae, adult-onset, OMIM:621424 & AR Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191 (OMIM accessed 9th Oct 2026).; to: PMID: 32548278 Yasuda et al., 2020 Report of a 37-year-old Japanese woman with headache, memory loss, mild flexion of retinal vessels, and gait disturbance. She was born to consanguineous parents. Her symptoms started at 22 yrs with a migraine. Brain MRI showed a cerebral white matter lesion at age 30 years. Wechsler Adult Intelligence Scale–Third Edition indicated a full-scale IQ of 69 - borderline ID. Seq method: targeted exome seq of 115 genes. She was found to be homozygous for LAMB1: c.1378T>C, p.Cys460Arg variant. Parents confirmed het. There is only 1 het individual reported in gnomAD v4.1.2 with this variant. Authors pose that "the effect of missense mutations on the phenotype may be milder compared with that of frameshift mutations." Functional support: PMID: 40237576 Yasuda et al., 2025 - Drosophila melanogaster model. Study found that the LAMB1 fly ortholog LanB1 gene is expressed on the surface of adult fly brains in a subset of glia cells. While human LAMB1 was not able to function in flies, in vivo overexpression and rescue experiments using analogous variants in fly LanB1 suggested that the frameshift variants behave as strong LoF alleles whereas a missense variant functions as a milder LoF allele. LAMB1 is associated with AD Leukoencephalopathy without lacunae, adult-onset, OMIM:621424 & AR Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191 (OMIM accessed 9th Oct 2026). |
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| Neurodegenerative disorders, adult onset v9.25 | LAMB1 | Ida Ertmanska reviewed gene: LAMB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32548278; Phenotypes: Leukoencephalopathy without lacunae, adult-onset, OMIM:621424, leukoencephalopathy without lacunae, adult-onset, MONDO:0980752, Leukoencephalopathy with variable cortical brain malformations and/or hydrocephalus, OMIM:615191; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.44 | SYP | Ida Ertmanska commented on gene: SYP: Comment on list classification: As reviewed by Julie Evans, there is little evidence published after 2009 for the association between SYP and X-linked intellectual disability. Two more recent cases reported in PMIDs: 32193494 & 34310040 had additional potentially causal variants in genes other than SYP. Hence, this gene is tagged for demotion to Amber, with a request for additional expert review to ensure NHS-wide agreement on the strength of this evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.44 | SYP | Ida Ertmanska Phenotypes for gene: SYP were changed from Mental Retardation, X-linked; Mental retardation, X-linked 96, 300802; MENTAL RETARDATION X-LINKED SYP-RELATED (MRXSYP) to Intellectual developmental disorder, X-linked 96, OMIM:300802; intellectual disability, X-linked 96, MONDO:0010429 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.43 | SYP | Ida Ertmanska Publications for gene: SYP were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.42 | SYP |
Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: SYP. Tag Q3_26_expert_review tag was added to gene: SYP. |
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| Severe microcephaly v9.37 | COPB2 | Ida Ertmanska Publications for gene: COPB2 were set to 29036432 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.36 | COPB2 | Ida Ertmanska Phenotypes for gene: COPB2 were changed from Microcephaly, HP:0000252 to ?Microcephaly 19, primary, autosomal recessive, OMIM:617800; microcephaly 19, primary, autosomal recessive, MONDO:0054716 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.17 | COPB2 | Ida Ertmanska Phenotypes for gene: COPB2 were changed from juvenile osteoporosis; Osteopenia; Osteoporosis; recurrent fractures to Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884; ?Microcephaly 19, primary, autosomal recessive, OMIM:617800; microcephaly 19, primary, autosomal recessive, MONDO:0054716; osteoporosis, childhood- or juvenile-onset, with developmental delay, MONDO:0859253 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.35 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). Osteogenesis imperfecta has been linked to chromosome 3p22-24.1 (PMID: 12110407). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Osteogenesis imperfecta v6.8 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). Osteogenesis imperfecta has been linked to chromosome 3p22-24.1 (PMID: 12110407). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Skeletal dysplasia v10.16 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). Osteogenesis imperfecta has been linked to chromosome 3p22-24.1 (PMID: 12110407). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Skeletal dysplasia v10.16 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). Osteogenesis imperfecta has been linked to chromosome 3p22-24.1 (PMID: 12110407). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Osteogenesis imperfecta v6.8 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). Osteogenesis imperfecta has been linked to chromosome 3p22-24.1 (PMID: 12110407). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Severe microcephaly v9.35 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). Osteogenesis imperfecta has been linked to chromosome 3p22-24.1 (PMID: 12110407). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Skeletal dysplasia v10.16 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Severe microcephaly v9.35 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Osteogenesis imperfecta v6.8 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026). |
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| Skeletal dysplasia v10.16 | COPB2 | Ida Ertmanska Publications for gene: COPB2 were set to 34450031; 29036432 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.15 | COPB2 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: COPB2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v6.8 | COPB2 | Ida Ertmanska changed review comment from: There are now two unrelated probands reported with the same homozygous missense COPB2 variant. However, only one of the probands had osteopenia - no skeletal issues noted in PMID: 37734708. Hence, the MOI should remain MONOALLELIC, until more evidence emerges.; to: Comment on mode of inheritance: There are now two unrelated probands reported with the same homozygous missense COPB2 variant. However, only one of the probands had osteopenia - no skeletal issues noted in PMID: 37734708. Hence, the MOI should remain MONOALLELIC, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.15 | COPB2 | Ida Ertmanska commented on gene: COPB2: Comment on mode of inheritance: There are now two unrelated probands reported with the same homozygous missense COPB2 variant. However, only one of the probands had osteopenia (without fractures) - no skeletal issues noted in PMID: 37734708. Hence, the MOI should be changed back to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.15 | COPB2 | Ida Ertmanska reviewed gene: COPB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29036432, 37734708; Phenotypes: Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884, ?Microcephaly 19, primary, autosomal recessive, OMIM:617800, microcephaly 19, primary, autosomal recessive, MONDO:0054716, osteoporosis, childhood- or juvenile-onset, with developmental delay, MONDO:0859253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.35 | COPB2 | Ida Ertmanska changed review comment from: Comment on list classification: There are now two unrelated probands reported with biallelic COPB2 variants and severe microcephaly. Hence, the gene can be rated Amber.; to: Comment on list classification: There are now two unrelated probands reported with the same homozygous missense COPB2 variant and severe microcephaly. Hence, the gene can be rated Amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v6.8 | COPB2 | Ida Ertmanska commented on gene: COPB2: There are now two unrelated probands reported with the same homozygous missense COPB2 variant. However, only one of the probands had osteopenia - no skeletal issues noted in PMID: 37734708. Hence, the MOI should remain MONOALLELIC, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v6.8 | COPB2 | Ida Ertmanska Tag watchlist_moi was removed from gene: COPB2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.35 | COPB2 | Ida Ertmanska changed review comment from: Comment on list classification: There are now two unrelated probands reported with biallelic COPB2 variants and severe microcephaly. Hence, the gene can now be rated Amber.; to: Comment on list classification: There are now two unrelated probands reported with biallelic COPB2 variants and severe microcephaly. Hence, the gene can be rated Amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.35 | COPB2 | Ida Ertmanska Classified gene: COPB2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.35 | COPB2 | Ida Ertmanska Added comment: Comment on list classification: There are now two unrelated probands reported with biallelic COPB2 variants and severe microcephaly. Hence, the gene can now be rated Amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.35 | COPB2 | Ida Ertmanska Gene: copb2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.34 | COPB2 | Ida Ertmanska reviewed gene: COPB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29036432, 37734708; Phenotypes: ?Microcephaly 19, primary, autosomal recessive, OMIM:617800, microcephaly 19, primary, autosomal recessive, MONDO:0054716; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v6.8 | COPB2 | Ida Ertmanska edited their review of gene: COPB2: Changed publications to: 29036432, 37734708 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v6.8 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19). |
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| Osteogenesis imperfecta v6.8 | COPB2 |
Ida Ertmanska changed review comment from: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American proband reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.; to: PMID: 37734708 Shiri et al., 2023 Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected. |
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| Osteogenesis imperfecta v6.8 | COPB2 | Ida Ertmanska reviewed gene: COPB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37734708; Phenotypes: Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884, ?Microcephaly 19, primary, autosomal recessive, OMIM:617800, microcephaly 19, primary, autosomal recessive, MONDO:0054716, osteoporosis, childhood- or juvenile-onset, with developmental delay, MONDO:0859253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.12 | ISCU | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available (two unrelated cases and functional evidence from patient cells and yeast) for the association of monoallelic variants with metabolic myopathy. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.12 | ISCU | Achchuthan Shanmugasundram Mode of inheritance for gene: ISCU was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.11 | ISCU | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: ISCU. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.11 | ISCU | Achchuthan Shanmugasundram Phenotypes for gene: ISCU were changed from Myopathy with lactic acidosis, hereditary, OMIM:255125 to Myopathy with lactic acidosis, hereditary, OMIM:255125; hereditary myopathy with lactic acidosis due to ISCU deficiency, MONDO:0009706 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.10 | ISCU | Achchuthan Shanmugasundram Publications for gene: ISCU were set to 21165651; 22125086; 29079705 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.9 | ISCU | Achchuthan Shanmugasundram reviewed gene: ISCU: Rating: GREEN; Mode of pathogenicity: None; Publications: 29079705, 40529812; Phenotypes: Myopathy with lactic acidosis, hereditary, OMIM:255125, hereditary myopathy with lactic acidosis due to ISCU deficiency, MONDO:0009706; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.9 | DYSF |
Achchuthan Shanmugasundram changed review comment from: PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants. PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second patient, who was previously active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available. PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele. PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay. Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.; to: PMID:17287450 (2007) reported two unrelated patients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients were identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compound heterozygous or homozygous variants. PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second patient, who was previously active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available. PMID:29879922 (2018) reported a South African family of mixed descent in which all affected first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele. PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay. Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM. |
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| Likely inborn error of metabolism v9.38 | COQ5 | Achchuthan Shanmugasundram reviewed gene: COQ5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.38 | COQ5 |
Achchuthan Shanmugasundram Tag Q3_26_demote_amber was removed from gene: COQ5. Tag Q3_26_promote_green tag was added to gene: COQ5. |
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| Likely inborn error of metabolism v9.38 | COQ5 |
Achchuthan Shanmugasundram Tag Q2_26_promote_green was removed from gene: COQ5. Tag Q3_26_demote_amber tag was added to gene: COQ5. |
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| Likely inborn error of metabolism v9.38 | COQ5 | Achchuthan Shanmugasundram Entity copied from Mitochondrial disorders v10.25 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.38 | COQ5 |
Achchuthan Shanmugasundram gene: COQ5 was added gene: COQ5 was added to Likely inborn error of metabolism. Sources: Expert Review Amber,NHS GMS Q2_26_promote_green tags were added to gene: COQ5. Mode of inheritance for gene: COQ5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COQ5 were set to 29044765; 36266294; 37599337; 41199775 Phenotypes for gene: COQ5 were set to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; mitochondrial disease, MONDO:0044970 |
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| Proteinuric renal disease v6.22 | ISCA-37417-Loss | Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 unrelated male individuals with ichthyosis and renal disease including proteinuria, harbouring heterozygous deletions affecting the ISCA-37417-Loss region (particularly full STS deletions). Hence, this region should be promoted to Green at the next update.; to: Comment on list classification: There are at least 3 unrelated male individuals with ichthyosis and renal disease including proteinuria and nephrotic syndrome, harbouring heterozygous deletions affecting the ISCA-37417-Loss region (particularly full STS deletions). Hence, this region should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | MAP4K1 |
Boaz Palterer gene: MAP4K1 was added gene: MAP4K1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: MAP4K1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAP4K1 were set to 40716650 Phenotypes for gene: MAP4K1 were set to Recurrent fever; Arthritis; Rash; Arthralgia; Autoimmune disease; Lymphadenopathy; Splenomegaly Penetrance for gene: MAP4K1 were set to unknown Review for gene: MAP4K1 was set to RED Added comment: Kaustio et al. described multiple patients from two kindreds harboring heterozygous loss-of-function mutations in the MAP4K1 gene. They presented with recurrent fevers, systemic inflammatory symptoms (including an atypical Still disease/Kawasaki-like presentation), inflammatory arthritis, rash, arthralgia, and features of immune dysregulation. The underlying mechanism and phenotype were validated ex vivo and in vitro using patient-derived primary T cells and CRISPR-Cas9-engineered primary human T cells, demonstrating reduced HPK1 protein expression, defective SLP-76 phosphorylation at Ser376, hyperresponsiveness to T-cell receptor stimulation, and elevated secretion of proinflammatory cytokines (notably IFN-γ and TNF). The hyperactive T-cell phenotype was successfully recreated with CRISPR-Cas9 knockout of MAP4K1 in primary human T cells and was partially reversed following targeted genetic rescue/correction of the variant. Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v9.41 | ACO2 |
Ida Ertmanska changed review comment from: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous. ACO2 is associated with AR Infantile cerebellar-retinal degeneration, OMIM:614559 and AD Optic atrophy 9. OMIM:616289 in OMIM (accesssed 8th Oct 2026).; to: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 31106992 Fukada et al., 2019 Report of a Japanese female patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. WES detected comp het missense variants (c.1534G>A, p.Asp512Asn and c.1997G>C, p.Gly666Ala) in ACO2. Parents were healthy and unrelated, confirmed to be het for a variant each. PMID: 25351951 Metodiev et al., 2014 Study of 5 patients from 3 unrelated families with homozygous or compound heterozygous missense and frameshift mutations in ACO2, with either isolated or syndromic optic neuropathy. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous. ACO2 is associated with AR Infantile cerebellar-retinal degeneration, OMIM:614559 and AD Optic atrophy 9. OMIM:616289 in OMIM (accesssed 8th Oct 2026). |
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| Ataxia and cerebellar anomalies - childhood onset v9.41 | ACO2 | Ida Ertmanska edited their review of gene: ACO2: Changed publications to: 22405087, 25351951, 31106992, 32519519, 34056600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.41 | ACO2 | Ida Ertmanska commented on gene: ACO2: Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in ACO2. Individuals with heterozygous ACO2 variants present with isolated optic atrophy, while those with biallelic variants may present with either syndromic or non-syndromic optic atrophy. Syndromic presentation usually involves cerebellar-retinal degeneration, ataxia, seizures, ID, and developmental delays. Hence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Ataxia and cerebellar anomalies - childhood onset. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.42 | ACO2 | Ida Ertmanska commented on gene: ACO2: Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in ACO2. Individuals with heterozygous ACO2 variants present with isolated optic atrophy, while those with biallelic variants may present with either syndromic or non-syndromic optic atrophy. Syndromic presentation usually involves cerebellar-retinal degeneration, ataxia, seizures, ID, and developmental delays. Hence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.42 | ACO2 | Ida Ertmanska edited their review of gene: ACO2: Changed publications to: 22405087, 25351951, 31106992, 32519519, 34056600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.42 | ACO2 |
Ida Ertmanska changed review comment from: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous. ACO2 is associated with AR Infantile cerebellar-retinal degeneration, OMIM:614559 and AD Optic atrophy 9. OMIM:616289 in OMIM (accesssed 8th Oct 2026).; to: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 31106992 Fukada et al., 2019 Report of a Japanese female patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. WES detected comp het missense variants (c.1534G>A, p.Asp512Asn and c.1997G>C, p.Gly666Ala) in ACO2. Parents were healthy and unrelated, confirmed to be het for a variant each. PMID: 25351951 Metodiev et al., 2014 Study of 5 patients from 3 unrelated families with homozygous or compound heterozygous missense and frameshift mutations in ACO2, with either isolated or syndromic optic neuropathy. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous. ACO2 is associated with AR Infantile cerebellar-retinal degeneration, OMIM:614559 and AD Optic atrophy 9. OMIM:616289 in OMIM (accesssed 8th Oct 2026). |
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| Ataxia and cerebellar anomalies - childhood onset v9.41 | ACO2 |
Ida Ertmanska changed review comment from: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous.; to: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous. ACO2 is associated with AR Infantile cerebellar-retinal degeneration, OMIM:614559 and AD Optic atrophy 9. OMIM:616289 in OMIM (accesssed 8th Oct 2026). |
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| Intellectual disability v11.42 | ACO2 |
Ida Ertmanska changed review comment from: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous.; to: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous. ACO2 is associated with AR Infantile cerebellar-retinal degeneration, OMIM:614559 and AD Optic atrophy 9. OMIM:616289 in OMIM (accesssed 8th Oct 2026). |
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| Intellectual disability v11.42 | ACO2 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: ACO2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.41 | ACO2 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: ACO2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.42 | ACO2 | Ida Ertmanska Publications for gene: ACO2 were set to 22405087; 25351951; 34056600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.41 | ACO2 | Ida Ertmanska Publications for gene: ACO2 were set to 26992325; 28545339; 30689204; 32519519 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.40 | ACO2 | Ida Ertmanska reviewed gene: ACO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22405087, 32519519, 34056600; Phenotypes: Infantile cerebellar-retinal degeneration, OMIM:614559, Optic atrophy 9. OMIM:616289; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.41 | ACO2 | Ida Ertmanska edited their review of gene: ACO2: Changed publications to: 22405087, 32519519, 34056600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.41 | ACO2 |
Ida Ertmanska changed review comment from: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2.; to: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. PMID: 22405087 Spiegel et al., 2012 Studied eight individuals from two unrelated families of Arab Muslim origin who presented at 2–6 months of age with truncal hypotonia and athetosis, seizure disorder, profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Six individuals older than 2 years were profoundly intellectually disabled. All patients were homozygous for ACO2 p.Ser112Arg. Method: homozygosity mapping and WES. Ten parents and one of the healthy sibs were confirmed to be heterozygous. |
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| Intellectual disability v11.41 | ACO2 |
Ida Ertmanska changed review comment from: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort.; to: PMID: 34056600 Charif et al., 2021 Study identified 61 cases harbouring variants in ACO2. 50/61 harboured heterozygous ACO2 variants. 52 individuals had isolated optic atrophy. "27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy (...) with a single case showing hearing loss (P38) and two cases showing a late-onset cerebellar ataxia (P19 and P53)." However, extraocular features in the dominant cases were not consistent and mostly did not match the AR Infantile cerebellar-retinal degeneration disease entity associated with ACO2 - probably incidental findings. P19 - somewhat consistent - het for ACO2 p.Gly463Arg and had cerebellar ataxia. Among recessive cases, 1 individual had epilepsy with onset at 22 yrs (comp het for ACO2 c.36+5delG and p.(Gly240Ala)). Another patient presented with kinetic and static cerebellar syndrome with cerebellar atrophy; episode of dysarthria at 45 y - comp het for ACO2 p.(Leu74Val) and p.(Glu464*). No mention of intellectual disability in this cohort. PMID: 32519519 Blackburn et al., 2020 Report of five patients with biallelic pathogenic variants in ACO2: Case 1 & 2 - Two sibs with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities. Case 3 - proband presented with the classic form with cerebellar hypoplasia, ataxia, seizures, moderate‐to‐severe intellectual disability, optic atrophy, and retinitis pigmentosa. Case 4 - proband demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Case 5 - proband presented with ataxia, severe developmental and motor delays, and seizures; developed severe progressive spastic quadriplegia. Mostly missense variants; Case 5 had biallelic frameshift variants in ACO2. |
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| Intellectual disability v11.41 | ACO2 | Ida Ertmanska reviewed gene: ACO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34056600; Phenotypes: Infantile cerebellar-retinal degeneration, OMIM:614559, Optic atrophy 9. OMIM:616289; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.46 | YARS |
Ida Ertmanska changed review comment from: PMID: 38125821 Kuan et al., 2023 Report of a Hispanic individual with dysmorphic facies and neurological issues. Admitted in the neonatal period due to seizure-like activity, vomiting, and poor feeding. Brain MRI yielded no significant findings. An abdominal ultrasound revealed an echogenic liver. He had hearing loss in his left ear. Subsequently diagnosed with microcephaly, hypotonia, nystagmus, and significant developmental delays. A microarray conducted shortly after birth revealed 47, XXY. WES uncovered a paternally inherited YARS: c.1099C > T, p.Arg367Trp variant & a maternally inherited YARS: c.782T > G, p.Leu261Arg. Father has history of hearing loss and neurological symptoms; mother was unaffected. PMID: 34536092 Averdunk et al., 2021 Study identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) in YARS. Patients presented with a multisystem disorder with developmental delay (12/12), microcephaly (12/12), failure to thrive, short stature, muscular hypotonia (9/12), ataxia, brain anomalies, microcytic anemia (8/8 assessed), hepatomegaly (7/7 assessed), and hypothyroidism. Seq method: exome sequencing. Haplotype analysis showed that the haplotype of individuals originating from Saudi Arabia (C-I) differs from the haplotypes of individuals A + B (from Turkey) and L (from Puerto Rico) - supportive of a recurrent rather than a founder variant. 2 unrelated individuals had hearing loss. PMID 30304524 Williams et al., 2019 Report of 7 related Amish children homozygous for YARS, c.499C>A, p.Pro167Thr (seq method: WES). Phenotype: poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Bilateral sensorineural hearing loss and cholestatic liver disease were present in 7/7 affected individuals. Related adult het carriers were asymptomatic. PMID: 29232904 Tracewska-Siemiątkowska et al., 2017 Report of a Swedish proband homozygous for YARS: c.806T>C, p.(F269S). Method: Trio WES. Phenotype of the proband: progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. Het parents unaffected.; to: PMID: 38125821 Kuan et al., 2023 Report of a Hispanic individual with dysmorphic facies and neurological issues. Admitted in the neonatal period due to seizure-like activity, vomiting, and poor feeding. Brain MRI yielded no significant findings. An abdominal ultrasound revealed an echogenic liver. He had hearing loss in his left ear. Subsequently diagnosed with microcephaly, hypotonia, nystagmus, and significant developmental delays. Laboratory tests indicated anemia. A microarray conducted shortly after birth revealed 47, XXY. WES uncovered a paternally inherited YARS: c.1099C > T, p.Arg367Trp variant & a maternally inherited YARS: c.782T > G, p.Leu261Arg. Father has history of hearing loss and neurological symptoms; mother was unaffected. PMID: 34536092 Averdunk et al., 2021 Study identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) in YARS. Patients presented with a multisystem disorder with developmental delay (12/12), microcephaly (12/12), failure to thrive, short stature, muscular hypotonia (9/12), ataxia, brain anomalies, microcytic anemia (8/8 assessed), hepatomegaly (7/7 assessed), and hypothyroidism. Seq method: exome sequencing. Haplotype analysis showed that the haplotype of individuals originating from Saudi Arabia (C-I) differs from the haplotypes of individuals A + B (from Turkey) and L (from Puerto Rico) - supportive of a recurrent rather than a founder variant. 2 unrelated individuals had hearing loss. PMID 30304524 Williams et al., 2019 Report of 7 related Amish children homozygous for YARS, c.499C>A, p.Pro167Thr (seq method: WES). Phenotype: poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Bilateral sensorineural hearing loss and cholestatic liver disease were present in 7/7 affected individuals. Related adult het carriers were asymptomatic. PMID: 29232904 Tracewska-Siemiątkowska et al., 2017 Report of a Swedish proband homozygous for YARS: c.806T>C, p.(F269S). Method: Trio WES. Phenotype of the proband: progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. Het parents unaffected. |
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| Monogenic hearing loss v6.46 | YARS | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 8th Oct 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.46 | YARS | Ida Ertmanska Phenotypes for gene: YARS were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375; hearing loss disorder, MONDO:0005365 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375; hearing loss disorder, MONDO:0005365 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.41 | YARS | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 8th Oct 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.41 | YARS | Ida Ertmanska Phenotypes for gene: YARS were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.19 | YARS | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 8th Oct 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.19 | YARS | Ida Ertmanska Phenotypes for gene: YARS were changed from Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.40 | YARS | Ida Ertmanska Phenotypes for gene: YARS were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.40 | YARS | Ida Ertmanska Phenotypes for gene: YARS were changed from Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.39 | YARS | Ida Ertmanska Publications for gene: YARS were set to 30304524; 29232904; 27633801 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.38 | YARS |
Ida Ertmanska Tag watchlist was removed from gene: YARS. Tag Q4_26_promote_green tag was added to gene: YARS. |
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| Intellectual disability v11.38 | YARS | Ida Ertmanska commented on gene: YARS: Comment on list classification: There are now at least 5 unrelated probands reported in literature with biallelic YARS (new name YARS1) variants and a multisystem disorder including significant developmental delays. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.45 | YARS | Ida Ertmanska commented on gene: YARS: Comment on list classification: There are now at least 5 unrelated probands reported in literature with biallelic YARS (new name YARS1) variants and a multisystem disorder including hearing loss. Hence, this gene can be promoted to Green on Monogenic hearing loss. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.38 | YARS | Ida Ertmanska reviewed gene: YARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 29232904, 30304524, 34536092, 38125821; Phenotypes: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418, neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.45 | YARS | Ida Ertmanska Phenotypes for gene: YARS were changed from Charcot-Marie-Tooth disease, dominant intermediate C 608323; Intellectual disability; deafness; nystagmus; liver dysfunction to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375; hearing loss disorder, MONDO:0005365 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.44 | YARS | Ida Ertmanska Publications for gene: YARS were set to 30304524; 29232904; 27633801 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.43 | YARS |
Ida Ertmanska Tag watchlist was removed from gene: YARS. Tag Q4_26_promote_green tag was added to gene: YARS. |
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| Monogenic hearing loss v6.43 | YARS | Ida Ertmanska edited their review of gene: YARS: Changed phenotypes to: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418, neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2, MONDO:0030375 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.43 | YARS | Ida Ertmanska edited their review of gene: YARS: Changed publications to: 29232904, 30304524, 34536092, 38125821; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.43 | YARS | Ida Ertmanska reviewed gene: YARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.11 | SLC2A1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported.; to: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Also, both recessive cases had symptom onset in early childhood. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.40 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.40 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.89 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from Dystonia 9 601042 AD; GLUT1 deficiency syndrome 1, infantile onset, severe 606777 AD, AR; GLUT1 deficiency syndrome 2, childhood onset 612126 AD; Stomatin-deficient cryohydrocytosis with neurologic defects 608885 AD; {Epilepsy, idiopathic generalized, susceptibility to, 12} 614847 to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.88 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to 22282645; 20574033; 21832227 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.39 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from Dystonia 9, 601042; GLUT1 deficiency syndrome 1, infantile onset, severe, 606777; GLUT1 deficiency syndrome 2, childhood onset, 612126; Stomatin-deficient cryohydrocytosis with neurologic defects, 608885 to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.38 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from GLUT1 deficiency syndrome 1, 606777; GLUT1 deficiency syndrome 2, 612126; {Epilepsy, idiopathic generalized, suscpetibility to, 12}, 614847; Dystonia 9, 601042; GLUT1 DEFICIENCY SYNDROME TYPE 1 (GLUT1DS1) to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.87 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.37 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.19 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.38 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.87 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.38 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20221955, 20687207, 41561681; Phenotypes: GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126, childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805, GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724, Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.87 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20221955, 20687207, 41561681; Phenotypes: GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126, childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805, GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724, Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20221955, 20687207, 41561681; Phenotypes: GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126, childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805, GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724, Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.15 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to 10980529; 18451999; 19630075; 18577546; 20210980529; 20221955; 20687207; 4156168121955; 20687207; 41561681 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.14 | SLC2A1 | Ida Ertmanska edited their review of gene: SLC2A1: Changed publications to: 10980529, 20221955, 20687207, 41561681 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.14 | SLC2A1 | Ida Ertmanska edited their review of gene: SLC2A1: Changed publications to: 10980529, 20221955, 20687207, 41561681, 20687207, 41561681 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.14 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to 10980529; 18451999; 19630075; 18577546; 20210980529; 20221955; 20687207; 4156168121955; 20687207; 41561681 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.13 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from paroxysmal exertion-induced dyskinesia with or without epilepsy and/or hemolytic anemia; GLUT1 DEFICIENCY SYNDROME 1; dystonia 9; GLUT1 deficiency syndrome 2, 612126; GLUT1 deficiency syndrome 1, 606777; Dystonia 9, 601042; EPILEPSY, IDIOPATHIC GENERALIZED to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.12 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to 18451999; 19630075; 18577546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.11 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.11 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Also, both recessive cases had disease onset in early childhood. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.11 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20210980529, 20221955, 20687207, 4156168121955, 20687207, 41561681; Phenotypes: GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126, childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805, GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724, Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.19 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from GLUT1 deficiency syndrome 1, 606777; GLUT1 deficiency syndrome 2, childhood onset; dystonia 9; EPILEPSY, IDIOPATHIC GENERALIZED; GLUT1 deficiency syndrome 1, infantile onset, severe; Dystonia; paroxysmal exertion-induced dyskinesia with or without epilepsy and/or hemolytic anemia; GLUT1 deficiency syndrome 2 to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.18 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to 19630075; 20301334; 18451999; 18577546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.17 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.17 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20221955, 20687207, 41561681; Phenotypes: GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126, childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805, GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724, Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.9 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to 18451999; 19630075; 18577546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.8 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.8 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.8 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20221955, 20687207, 41561681; Phenotypes: GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126, childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805, GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724, Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.8 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from EPILEPSY, IDIOPATHIC GENERALIZED; Dystonia 9 (paroxysmal choreoathetosis with episodic ataxia), 601042; paroxysmal exertion-induced dyskinesia with or without epilepsy and/or hemolytic anemia; GLUT1 deficiency syndrome 2, childhood onset, 612126; GLUT1 deficiency syndrome 1, infantile onset, severe, 606777 to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.11 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to 18451999; http://www.ncbi.nlm.nih.gov/books/NBK1155/; 19630075; 18577546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.10 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.10 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.10 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). The same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Dystonia, chorea or related movement disorder, adult onset v6.10 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20221955, 20687207, 41561681; Phenotypes: GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.10 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from Dystonia 9, OMIM:601042; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126 to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.37 | SLC2A1 | Ida Ertmanska Phenotypes for gene: SLC2A1 were changed from Intellectual disability; Early onset dystonia; Cataracts; Glucose transporter 1 deficiency (blood-brain barrier) (Disorders of glucose transport); Hereditary ataxia; Epileptic encephalopathy; Familial Genetic Generalised Epilepsies; GLUT1 deficiency syndrome 1, infantile onset, severe, 606777; GLUT1 deficiency syndrome 2, childhood onset, 612126 to GLUT1 deficiency syndrome 2, childhood onset, OMIM:612126; childhood onset GLUT1 deficiency syndrome 2, MONDO:0012805; GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777; encephalopathy due to GLUT1 deficiency, MONDO:0011724; Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.36 | SLC2A1 | Ida Ertmanska Publications for gene: SLC2A1 were set to 27604308 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.11 | FGF8 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 HPE families is confounded consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 HPE families is confounded by consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | SLC2A1 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: SLC2A1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | SLC2A1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel.; to: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel, until more biallelic cases are reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | SLC2A1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel.; to: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. While their heterozygous family members were reported as asymptomatic, GLUT1DS presents with variable and often mild symptoms. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. Study highlights that "GLUT1DS presents with variable symptoms, often unrecognised or too mild to prompt clinical attention." Several adults in the study were diagnosed in adulthood - some asymptomatic and only following their child’s diagnosis. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Likely inborn error of metabolism v9.35 | SLC2A1 | Ida Ertmanska edited their review of gene: SLC2A1: Changed publications to: 10980529, 20221955, 20687207, 41561681 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 41561681 Previtali et al., 2026 - MONOALLELIC COHORT Retrospective evaluation of 32 adults with genetically confirmed GLUT1DS from Italian medical centres. 17/32 variants in SLC2A1 were confirmed to be de novo, 10 inherited from a parent, and 5 of unknown inheritance. 24/32 patients had epilepsy, 26 had paroxysmal movement disorders. Fatigue was present in 12 individuals and migraine in 6. Psychomotor delay was observed in 15/32 subjects. Subsequently, 11/32 individuals received a diagnosis of intellectual disability. Mean age at symptom onset was 4 yrs. Brain MRI was unremarkable in most cases (15/20). Mostly missense variants detected. BIALLELIC CASES: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Likely inborn error of metabolism v9.35 | SLC2A1 | Ida Ertmanska commented on gene: SLC2A1: Comment on mode of inheritance: There are numerous patients reported in literature with monoallelic SLC2A1 variants and GLUT1 deficiency syndrome (characterised by early-onset epileptic encephalopathy associated with hypoglycorrhachia, delayed development, acquired microcephaly, motor incoordination, and spasticity). There are only two probands reported to date with biallelic SLC2A1 variants and GLUT1 deficiency syndrome. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). Variants R126L (SLC2A1 c.377G>T (p.Arg126Leu)) & K256V (SLC2A1: c.766_767delinsGT (p.Lys256Val)) are not reported in gnomAD v4.1.2. SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Likely inborn error of metabolism v9.35 | SLC2A1 |
Ida Ertmanska changed review comment from: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (R126L inherited from an asymptomatic mother). SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026).; to: PMID: 20687207 Rotstein et al., 2011 F1 - male proband seen at 3 yrs, with seizures, dev delay, progressive postnatal microcephaly, hypoglycorrhachia on CSF analysis. He had spasticity with distant lower limb dystonia. Parents and sister unaffected. He was found to carry comp het SLC2A1 (old name GLUT1) variants: c.945A>G, p.K256V (maternally inherited) and c.556G>T, p.R126L (de novo). Looks to be the same patient as P13 in PMID: 10980529. F2 - two affectes sisters, aged 6 and 2.5 yrs. Seems to be the same family as in PMID: 20221955. Only SLC2A1 was analysed, method not described. PMID: 20221955 Klepper et al., 2009 Report of a 6yo female patient from a consanguineous Arab family from Qatar, with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Symptom onset was around 18 months of age, with frequent falls and an ataxic gait. She harboured a homozygous SLC2A1: c.1402C>T (p.Arg468Trp) variant - also homozygous in her younger sister who was asymptomatic. Unaffected parents were het for the variant. 3 hets reported in gnomAD v4.1.2, no hmz. Method: targeted sequencing of SLC2A1. PMID: 10980529 Wang et al., 2000 Report of 15 children with infantile seizures, acquired microcephaly, low CSF/blood glucose ratio, and dev delay, harbouring SLC2A1 variants. Method: PCR sequencing of SLC2A1 only. 7 patients had het nonsense variants in SLC2A1, 3 had splicing variants, and 1 harboured a large deletion. 4 patients had missense variants, including Patient 13 with comp het SLC2A1 variants R126L and K256V (K256V inherited from an asymptomatic mother). SLC2A1 association with AD GLUT1 deficiency syndrome is classified as Definitive in ClinGen (Intellectual Disability and Autism GCEP, Apr 2019). The gene is associated with several disease entities in OMIM: AD {Epilepsy, idiopathic generalized, susceptibility to, 12}, MIM:614847; AD Dystonia 9, MIM:601042; AD GLUT1 deficiency syndrome 2, childhood onset, MIM:612126; AD, AR GLUT1 deficiency syndrome 1, infantile onset, severe, MIM:606777; AD Stomatin-deficient cryohydrocytosis with neurologic defects, OMIM:608885 (accessed 7th Oct 2026). |
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| Likely inborn error of metabolism v9.35 | SLC2A1 | Ida Ertmanska reviewed gene: SLC2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10980529, 20221955, 20687207; Phenotypes: GLUT1 deficiency syndrome 1, infantile onset, severe, OMIM:606777, encephalopathy due to GLUT1 deficiency, MONDO:0011724; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.25 | GBA | Eleanor Williams commented on gene: GBA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | AP1M2 |
Boaz Palterer gene: AP1M2 was added gene: AP1M2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: AP1M2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP1M2 were set to 41451456 Phenotypes for gene: AP1M2 were set to Colitis; Abnormal inflammatory response Penetrance for gene: AP1M2 were set to unknown Review for gene: AP1M2 was set to RED Added comment: Jin et al. described 1 patient from 1 kindred, harboring biallelic mutations in the AP1M2 gene. They presented with an autoinflammatory disease and colitis. The underlying mechanism and phenotype were validated in vitro and in vivo using patient-derived samples and KO mouse models, demonstrating a loss of AP-1-mediated suppression of NF-κB activation and excessive chemokine production. The autoinflammatory and colitis phenotype was successfully recreated with complete knockout (KO) models. Sources: Literature |
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| Fetal anomalies v8.17 | PAX6 | Achchuthan Shanmugasundram Publications for gene: PAX6 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.20 | SIGMAR1 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SIGMAR1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.20 | SIGMAR1 | Achchuthan Shanmugasundram Classified gene: SIGMAR1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.20 | SIGMAR1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Luke Stuart, there is sufficient evidence available for the association of biallelic SIGMAR1 variants with distal hereditary motor neuronopathy 2. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.20 | SIGMAR1 | Achchuthan Shanmugasundram Gene: sigmar1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.19 | SIGMAR1 | Achchuthan Shanmugasundram Phenotypes for gene: SIGMAR1 were changed from ?Amyotrophic lateral sclerosis 16, juvenile 614373 to ?Neuronopathy, distal hereditary motor, autosomal recessive 2, OMIM:605726 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.18 | SIGMAR1 | Achchuthan Shanmugasundram Publications for gene: SIGMAR1 were set to 21842496 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.17 | SIGMAR1 |
Luke Stuart changed review comment from: SIGMAR1 is associated with autosomal recessive distal hereditary motor neuronopathy 2 (OMIM: 605726) (accessed 10/ 2026) Multiple unrelated patients and families with biallelic SIGMAR1 variants have been reported, typically presenting with early-onset, slowly progressive distal muscle weakness and atrophy, minimal or absent sensory involvement, and pyramidal signs (Li et al. 2015, PMID: 26078401; Lee et al. 2016, PMID: 28503617; Horga et al. 2016, PMID: 27629094; Ververis et al. 2020, PMID: 31511340). In the latter study, a homozygous missense mutation (c.500A>T, N167I) cosegregated with the dHMN phenotype in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. Recent evidence from six affected individuals in five unrelated Japanese families further supports biallelic SIGMAR1 variants as a cause of early-onset, motor-predominant axonal neuropathy with distal weakness and atrophy with pyramidal signs (Kodama et al. 2026, PMID: 42641169). Age of onset varied from <5 to 13 years of age. Functional evidence supports impaired or reduced SIGMAR1 function as the disease mechanism. Loss of function variants including SIGMAR1 c.151+1G>T (a recurrent splicing variant) and c.500A>T, p.(Asn167Ile) have been described, the latter showing reduced protein expression, altered subcellular distribution and increased cell death (Li et al. 2015, PMID: 26078401; Ververis et al. 2020, PMID: 31511340). Sigmar1-/- mice exhibit locomotor impairment, muscle weakness, axonal degeneration and motor-neuron loss, providing additional mechanistic support (Bernard-Marissal et al. 2015, PMID: 25678561) A green rating is thus recommended for paediatric motor neuropathy.; to: SIGMAR1 is associated with autosomal recessive distal hereditary motor neuronopathy 2 (OMIM: 605726) (accessed 10/ 2026) Multiple unrelated patients and families with biallelic SIGMAR1 variants have been reported, typically presenting with early-onset, slowly progressive distal muscle weakness and atrophy, minimal or absent sensory involvement, and pyramidal signs (Li et al. 2015, PMID: 26078401; Lee et al. 2016, PMID: 28503617; Horga et al. 2016, PMID: 27629094; Ververis et al. 2020, PMID: 31511340). In the latter study, a homozygous missense mutation (c.500A>T, N167I) cosegregated with the dHMN phenotype in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. Recent evidence from six affected individuals in five unrelated Japanese families further supports biallelic SIGMAR1 variants as a cause of early-onset, motor-predominant axonal neuropathy with distal weakness and atrophy with pyramidal signs (Kodama et al. 2026, PMID: 42641169). Age of onset varied from <5 to 13 years of age. Functional evidence supports impaired or reduced SIGMAR1 function as the disease mechanism. Loss of function variants including SIGMAR1 c.151+1G>T (a recurrent splicing variant) and c.500A>T, p.(Asn167Ile) have been described, the latter showing reduced protein expression, altered subcellular distribution and increased cell death (Li et al. 2015, PMID: 26078401; Ververis et al. 2020, PMID: 31511340). Sigmar1-/- mice exhibit locomotor impairment, muscle weakness, axonal degeneration and motor-neuron loss, providing additional mechanistic support (Bernard-Marissal et al. 2015, PMID: 25678561) A green rating is thus recommended for paediatric motor neuronopathy. |
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| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency. However, the evidence for the 3 HPE families is confounded consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 HPE families is confounded consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.11 | FGF8 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.11 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 31748124 - IHH Proband 15, male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 18596921 - Case 3 - IHH proband homozygous for FGF8 p.Phe40Leu variant. Additional FGFR1 mutations were also detected. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). |
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| Pituitary hormone deficiency v4.11 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed publications to: 18596921, 21045958, 21832120, 27363716, 29584859, 31748124 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed publications to: 18596921, 21045958, 21832120, 27363716, 29584859, 31748124 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 31748124 - IHH Proband 15, male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 18596921 - Case 3 - IHH proband homozygous for FGF8 p.Phe40Leu variant. Additional FGFR1 mutations were also detected. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). |
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| Pituitary hormone deficiency v4.11 | FGF8 | Ida Ertmanska commented on gene: FGF8: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency. However, the evidence for the 3 pituitary insufficiency probands is confounded consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska commented on gene: FGF8: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Holoprosencephaly. There are also at lesast 5 individuals reported in literature with biallelic FGF8 variants. Two probands had hypogonadotropic hypogonadism and three others presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency. However, the evidence for the 3 HPE families is confounded consanguinity and limited segregation evidence. Hence, the MOI should be remain as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted', until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.11 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.11 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed rating: GREEN; Changed publications to: 21045958, 21832120, 27363716, 29584859; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.11 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). No pituitary deficiency reported for these patients. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. |
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| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed rating: GREEN; Changed publications to: 21045958, 21832120, 27363716, 29584859; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. MONOALLELIC CASES: PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 27363716 Dubourg et al., 2016 Study screened a cohort of 257 HPE patients. 2.3% of patients had a FGF8 variant. - Fetus with semilobar HPE had a het FGF8 p.Thr199Met variant, along with a FGFR1 splice variant. - 4yo boy with semilobar HPE was het for FGF8 p.Ala106Glu (de novo) - 2 unrelated families with a het FGF8 p.Arg129* variant and alobar HPE / syntelencephaly. - 2 unrelated families with a het FGF8 p.Arg206Gln variant and lobar HPE, or microfom in the second family (where the variant cosegregated with another mutation in DLL1). PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. |
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| Holoprosencephaly v6.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4.; to: BIALLELIC CASE REPORTS: PMID: 29584859 Hong et al., 2018 Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 21045958 Arauz et al., 2010 Study screened 360 probands with HPE for sequence variations in FGF8. Described a family with HPE and a heterozygous (putative hypomorphic) FGF8 variant c.686C>T, p.T229M. Twins affected - one with semilobar HPE, microcephaly, cleft palate, seizures, diabetes insipidus (DI), and severe neurological impairment; the other twin had only single maxillary central incisor and hypotelorism. Mother was het for the same variant but only noted to have mild hypotelorism. No coding mutations found in SHH, ZIC2, SIX3, or TGIF. The same variant was reported in an IHH patient in PMID: 18596921. |
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| Pituitary hormone deficiency v4.11 | FGF8 | Ida Ertmanska reviewed gene: FGF8: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: hypogonadotropic hypogonadism 6 with or without anosmia, MONDO:0012988, Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed phenotypes to: hypogonadotropic hypogonadism 6 with or without anosmia, MONDO:0012988, Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | FGF8 | Ida Ertmanska commented on gene: FGF8 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.6 | FGF8 | Ida Ertmanska Phenotypes for gene: FGF8 were changed from Hypogonadotropic hypogonadism type 6 (OMIM 612702) to hypogonadotropic hypogonadism 6 with or without anosmia, MONDO:0012988; Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.5 | FGF8 | Ida Ertmanska Publications for gene: FGF8 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: FGF8. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed publications to: 18596921, 20463092, 21832120, 29584859, 31748124, 40508017 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Hypogonadotropic hypogonadism. There are also at 5 individuals reported in literature with biallelic FGF8 variants. However, three of them presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency, rather than hypogonadotropic hypogonadism. Another individual with biallelic FGF8 variants and IHH described in PMID: 18596921 harboured additional FGFR1 variants. Hence, there is little robust evidence for the association between biallelic FGF8 variants and HH, and the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal on this panel.; to: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Hypogonadotropic hypogonadism. There are also at 5 individuals reported in literature with biallelic FGF8 variants. However, three of them presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency, rather than hypogonadotropic hypogonadism. An individual with biallelic FGF8 variants and IHH, described in PMID: 18596921, harboured additional FGFR1 variants. Hence, there is little robust evidence for the association between biallelic FGF8 variants and HH, and the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Added comment: Comment on mode of inheritance: There is a well established association between herterozygous FGF8 variants and Hypogonadotropic hypogonadism. There are also at 5 individuals reported in literature with biallelic FGF8 variants. However, three of them presented with holoprosencephaly, diabetes insipidus, and pituitary insufficiency, rather than hypogonadotropic hypogonadism. Another individual with biallelic FGF8 variants and IHH described in PMID: 18596921 harboured additional FGFR1 variants. Hence, there is little robust evidence for the association between biallelic FGF8 variants and HH, and the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal on this panel.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured het variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured het variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509). |
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| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured het variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509). |
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| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. 2 hets with this variant reported in gnomAD v4. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Case 3 - homozygous for FGF8 p.Phe40Leu variant. Other cases had het FGF8 variants. Additional FGFR1 mutations were detected in cases 3 and 4. Functional: mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509). |
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| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He also had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509). |
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| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 31748124 Men et al., 2020 - HET & HMZ Study of a cohort of 145 Chinese IHH probands (125 men and 20 women). Seq method: WES + Sanger. Two novel mutations (p.E176K and p.R184C) reported in FGF8. Proband 14, male, carried a de novo FGF8 p.E176K mutation, as well as an AXL variant inherited from an unaffected mother. Proband 15 male, was homozygous for FGF8 p.R184C - consanguineous parents. He had hearing loss and testicular calcification. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509). |
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| Fetal anomalies v8.16 | PAX6 | Luke Stuart edited their review of gene: PAX6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. PMID: 18596921 Falardeau et al., 2008 461 unrelated IHH probands screened. Study identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes (candidate gene approach) - 3 familial and 3 sporadic cases. Additional FGFR1 mutations were detected in cases 3 and 4. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509). |
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| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 | Ida Ertmanska edited their review of gene: FGF8: Changed publications to: 20301509, 21832120, 29584859, 40508017 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026).; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). FGF8 variants account for <2% of persons with KS or normosmic isolated gonadotropin-releasing hormone deficiency (GeneReviews, PMID: 20301509). |
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| Fetal anomalies v8.16 | PAX6 |
Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Luke Stuart, there is sufficient evidence available for the association of PAX6 biallelic loss-of-function variants with a severe, prenatal/neonatal-onset neurodevelopmental disorder. Reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities. Monoallelic PAX6 variants are associated with developmental eye disorders, including aniridia, microphthalmia, coloboma and foveal hypoplasia. It is unclear whether monoallelic variants are relevant for the fetal anomalies panel. Hence, expert opinion is sought on whether the MOI should be updated to BOTH or Biallelic ONLY. |
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| Fetal anomalies v8.16 | PAX6 | Achchuthan Shanmugasundram Mode of inheritance for gene: PAX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 |
Ida Ertmanska changed review comment from: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 Cohort of patients with holoprosencephaly. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM.; to: PMID: 40508017 Chiarello et al., 2025 Congenital hypogonadotropic hypogonadism (CHH) cohort (14 patients). Seq method: NGS of 46 genes. Pt5 - female, 42yrs; presented with hypogonadism, primary amenorrhea, and anosmia; brain MRI showed hypoplasia of olfactory bulbs; she harboured variants in FGF8 (intronic variant chr10: g.103530393C>T) and IL17RD. Kallmann syndrome diagnosis. PMID: 29584859 Hong et al., 2018 - BIALLELIC Cohort of 330 patients with holoprosencephaly, sequenced using a targeted capture panel of 150 developmental genes. Patient 'BL11322' - homozygous for FGF8 p.T122M (consanguineous parents). Clinical features: seizures, dev delay, semilobar HPE, microcephaly, hypotelorism. Determined to be a hypomorph in a functional assay (zebrafish overexpression experiments). Patient 'Anonymous' - hmz for FGF8 p.R178H (consanguineous parents). Clinical features: dev delay, semilobar HPE, diabetes insipidus, pituitary insufficiency. PMID: 21832120 McCabe et al., 2011 - BIALLELIC Study objective: screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). FGF8 analysed by PCR and direct sequencing. A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. PMID: 20463092 Trarbach et al., 2010 2 het variants in FGF8 were identified in two unrelated IHH probands using targeted FGF8 seq. F1 = 5 sibs with KS / normosmic IHH / delayed puberty, het for p.R127X. Cleft lip and palate and neurosensorial deafness were also noted. F2 = proband is a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency; het for FGF8 p.R129X. FGF8 is associated with AD Hypogonadotropic hypogonadism 6 with or without anosmia 612702 in OMIM (accessed 7th Oct 2026). |
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| Paediatric motor neuronopathies v3.17 | SIGMAR1 | Luke Stuart reviewed gene: SIGMAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26078401, 28503617, 27629094, 31511340, 42641169, 25678561; Phenotypes: ?Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | FGF8 | Ida Ertmanska reviewed gene: FGF8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism 6 with or without anosmia, OMIM:612702; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.15 | PAX6 |
Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: PAX6. Tag Q3_26_MOI tag was added to gene: PAX6. |
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| Ataxia and cerebellar anomalies - childhood onset v9.38 | PAX6 | Achchuthan Shanmugasundram Classified gene: PAX6 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.38 | PAX6 |
Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Luke Stuart, there are two unrelated patients with heterozygous PAX6 variants and with evidence ataxia and/or a cerebellar syndrome phenotype. Although PAX6 knockout mice showed a primary role for PAX6 in cerebellar development, but did not recapitulate ataxia phenotype, nor cerebellar phenotype in the context of haploinsufficiency. There is sufficient evidence available for the association of PAX6 biallelic loss-of-function variants with a severe, prenatal/neonatal-onset neurodevelopmental disorder. However, reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities. Hence, this phenotype is not relevant for this panel. Hence, the gene should be demoted to amber and the MOI should be updated to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'. |
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| Ataxia and cerebellar anomalies - childhood onset v9.38 | PAX6 | Achchuthan Shanmugasundram Gene: pax6 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.25 | HSPB1 | Eleanor Williams changed review comment from: Removed tags for promotion and expert review for now, as this genes is part of a set of genes that clinically mimics progressive muscular atrophy, which will be part of a larger review of the panel content.; to: Removed tags for promotion and expert review for now, as this gene is part of a set of genes that clinically mimics progressive muscular atrophy, which will be part of a larger review of the panel content. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.25 | HSPB1 |
Eleanor Williams Tag Q3_26_expert_review was removed from gene: HSPB1. Tag Q3_26_NHS_review was removed from gene: HSPB1. Tag Q3_26_promote_green was removed from gene: HSPB1. |
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| Ataxia and cerebellar anomalies - childhood onset v9.37 | PAX6 |
Achchuthan Shanmugasundram Tag Q3_26_demote_amber tag was added to gene: PAX6. Tag Q3_26_expert_review tag was added to gene: PAX6. Tag Q3_26_MOI tag was added to gene: PAX6. |
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| Ataxia and cerebellar anomalies - childhood onset v9.37 | PAX6 | Achchuthan Shanmugasundram Phenotypes for gene: PAX6 were changed from Aniridia, Cerebellar Ataxia, And Mental Retardation to Aniridia, OMIM:106210; cerebellar ataxia, MONDO:0000437 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.36 | PAX6 | Achchuthan Shanmugasundram Publications for gene: PAX6 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.15 | LRP4 | Ida Ertmanska Phenotypes for gene: LRP4 were changed from Sclerosteosis 2 614305; Cenani-Lenz syndactyly syndrome 212780 to Cenani-Lenz syndactyly syndrome, OMIM:212780; Cenani-Lenz syndactyly syndrome, MONDO:0008931; Sclerosteosis 2, OMIM:614305; sclerosteosis 2, MONDO:0013679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.14 | LRP4 | Ida Ertmanska Publications for gene: LRP4 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.13 | LRP4 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: LRP4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.13 | LRP4 | Ida Ertmanska commented on gene: LRP4: Comment on mode of inheritance: There are numerous individuals reported in literature with biallelic LRP4 variants, presenting with either Sclerosteosis 2 or Cenani-Lenz syndactyly syndrome, with skeletal features such as bone overgrowth, phalangeal synostosis, shortened and disorganized metacarpals. There are also two individuals reported to date with skeletal and/or limb disorders, heterozygous for missense LRP4 variants - one of which was detected by targeted sequencing of LRP4 (other genes like SOST are known to cause a similar phenotype). In addition, heterozygous carriers of LRP4 missense variants in recessive pedigrees are always unaffected. Based on available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.8 | LRP4 | Ida Ertmanska commented on gene: LRP4: Comment on mode of inheritance: There are numerous individuals reported in literature with biallelic LRP4 variants, presenting with either Sclerosteosis 2 or Cenani-Lenz syndactyly syndrome, both of which affect distal limbs (polydactyly, phalangeal synostosis, syndactyly, oligodactyly). There are also two individuals reported to date with limb disorders and heterozygous missense LRP4 variants - one of which was detected by targeted sequencing of LRP4 (other genes like SOST are known to cause a similar phenotype). In addition, heterozygous carriers of LRP4 missense variants in recessive pedigrees are always unaffected. Based on available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.13 | LRP4 | Ida Ertmanska reviewed gene: LRP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21471202, 26751728, 30077757, 34857885, 35052419, 38013226, https://doi.org/10.1186/s43042-025-00783-837563890; Phenotypes: Cenani-Lenz syndactyly syndrome, OMIM:212780, Cenani-Lenz syndactyly syndrome, MONDO:0008931, Sclerosteosis 2, OMIM:614305, sclerosteosis 2, MONDO:0013679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.8 | LRP4 | Ida Ertmanska Phenotypes for gene: LRP4 were changed from Cenani-Lenz syndactyly syndrome, OMIM:212780; CLSS; Cenani syndactyly; Cenani-Lenz syndactyly; Syndactyly type 7; Polydactyly to Cenani-Lenz syndactyly syndrome, OMIM:212780; Cenani-Lenz syndactyly syndrome, MONDO:0008931; Sclerosteosis 2, OMIM:614305; sclerosteosis 2, MONDO:0013679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.7 | LRP4 | Ida Ertmanska Publications for gene: LRP4 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.6 | LRP4 | Ida Ertmanska Tag Q4_26_MOI tag was added to gene: LRP4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.6 | LRP4 |
Ida Ertmanska changed review comment from: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. Heterozygous variants were prioritised based on the pedigree. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing. P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant. BIALLELIC CASES: https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs. PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous. PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.; to: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. Heterozygous variants were prioritised based on the pedigree. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing. P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant. BIALLELIC CASES: https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs. PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous. PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp; sequenced 35 genes including SOST PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026. |
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| Limb disorders v9.6 | LRP4 | Ida Ertmanska edited their review of gene: LRP4: Changed publications to: 21471202, 26751728, 30077757, 34857885, 35052419, 38013226, https://doi.org/10.1186/s43042-025-00783-837563890 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.6 | LRP4 |
Ida Ertmanska changed review comment from: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing. P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant. BIALLELIC CASES: https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs. PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous. PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.; to: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. Heterozygous variants were prioritised based on the pedigree. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing. P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant. BIALLELIC CASES: https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs. PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous. PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026. |
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| Limb disorders v9.6 | LRP4 |
Ida Ertmanska changed review comment from: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails. Complications included such as dizziness, difficulties with gait and coordination, vertigo, and spastic and ataxic gait disturbances. Several neurological complications, such as facial nerve palsy and hearing loss, were present due to bone compression of cranial nerves. X-rays revealed severe thickening of the calvaria and the cortices of the long bones. Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant. LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026.; to: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth, using targeted LRP4 sequencing. P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails.Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant. BIALLELIC CASES: https://doi.org/10.1186/s43042-025-00783-8 - 5yo Sudanese male with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism (Cenani-Lenz syndrome). He harboured comp het LRP4 variants c.3813del; p.Thr1272Leufs*18) and (c.4910G > A; p.Cys1637Tyr). Shortened and disorganized metacarpals and phalanges seen on radiographs. PMID: 38013226 - Chinese individual with mild Cenani-Lenz syndactyly syndrome, homozygous for LRP4 p.(Asn94Lys) variant PMID: 35052419 - Spanish male patient with sclerosteosis and comp het LRP4 variants: p.Arg1170Gln and p.Arg632His; unaffected parents were het for one variant each PMID: 34857885 - three families of Pakistani origin with Cenani-Lenz syndrome and homozygous missense variants in LRP4: c.295G>C; p.(Asp99His) in two families and c.1633C>T; p.(Arg545Trp) in third family. Unaffected family members were heterozygous. PMID: 30077757 - Indian man with sclerosteosis, homozygous for LRP4 c.3508C > T, p.Arg1170Trp PMID: 26751728 - Portuguese man homozygous for LRP4 p.Arg1170Gln; no mutations in SOST; no DNA from parents LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026. |
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| Limb disorders v9.6 | LRP4 |
Ida Ertmanska changed review comment from: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails. Complications included such as dizziness, difficulties with gait and coordination, vertigo, and spastic and ataxic gait disturbances. Several neurological complications, such as facial nerve palsy and hearing loss, were present due to bone compression of cranial nerves. X-rays revealed severe thickening of the calvaria and the cortices of the long bones. Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant.; to: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails. Complications included such as dizziness, difficulties with gait and coordination, vertigo, and spastic and ataxic gait disturbances. Several neurological complications, such as facial nerve palsy and hearing loss, were present due to bone compression of cranial nerves. X-rays revealed severe thickening of the calvaria and the cortices of the long bones. Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant. LRP4 is associated with AR Cenani-Lenz syndactyly syndrome, MIM:212780; AR ?Myasthenic syndrome, congenital, 17, MIM:616304; AD, AR Sclerosteosis 2, MIM:614305 in OMIM. The association between LRP4 and AR Cenani-Lenz syndactyly syndrome was classified as Definitive (Apr 2023). It is Limited for association with AR congenital myasthenic syndrome 17 (Apr 2023). Resources accessed 7th Oct 2026. |
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| Fetal anomalies v8.15 | PAX6 |
Luke Stuart changed review comment from: Biallelic PAX6 variants are associated with severe congenital malformation including structural brain anomalies and aniridia. The paucity of patients reports reflects embryonic/ perinatal lethality associated with biallelic PAX6 loss of function. Glaser et al. 1994; PMID 7951315: A proband with compound heterozygous nonsense variants, c.607C>T (p.Arg203Ter) and c.1058C>G (p.Ser353Ter), presented with anophthalmia, microcephaly, complete agenesis of the corpus callosum and olfactory bulbs, hypoplasia of the cerebellum and pons, and died in the neonatal period. Solomon et al., 2010 (PMID 19876904): A surviving patient with compound heterozygous mutations in PAX6 presented with microphthalmia, neonatal diabetes mellitus, hypopituitarism, and microcephaly, as well as trisomy 21. The patient inherited a missense mutation affecting the paired domain from the father (c.112C>T, p.Arg38Trp), who had microcornea and severe cataracts, and a nonsense mutation in HD from the mother (c.718C>T, p.Arg240Ter), who presented with classical familial aniridia. Complex brain anomalies including absent corpus callosum, hypoplastic brainstem, near-absent olfactory bulbs, and polymicrogyria were noted. Schmidt-Sidor et al., 2009 (PMID 20054790) described a stillborn fetus; PAX6 c.117_128del12 (affecting the paired domain) and a frameshift variant, c.112delC, were identified in compound heterozygosity; autopsy revealed major CNS abnormalities including complete agenesis of the corpus callosum, cortical malformations and various cerebellar anomalies including cerebellar dysplasia; a similar phenotype was observed in a subsequent pregnancy. This severe CNS malformation phenotype is recapitulated in the Sey (Small eye) mouse, which carries a PAX6 LoF point mutation c.622G>T (p.Gly208Ter) (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)); Pax6 is produced in cerebellar granule cells and that PAX6 influences the morphogenesis of the whole cerebellum; homozygous Pax6Sey/Sey mice exhibit severe brain malformations, including cerebellar abnormalities, and die perinatally, whereas heterozygous Pax6Sey/+ mice survive and show developmental defects consistent with PAX6 haploinsufficiency. 3 unrelated patients are reported and the biallelic Sey mouse model recapitulates the human phenotype. Thus MOI comprising BOTH monoallelic and biallelic is proposed for the fetal anomalies panel.; to: Biallelic PAX6 variants are associated with severe congenital malformation including structural brain anomalies and aniridia. The paucity of patients reports reflects embryonic/ perinatal lethality associated with biallelic PAX6 loss of function. Monoallelic PAX6 pathogenic variants are associated with developmental eye disorders, including aniridia, microphthalmia, coloboma and foveal hypoplasia. Additional findings associated with PAX6-aniridia are variably reported, including Polymicrogyria (in 2/ 24 individuals reproted in PMID 12731001), structural brain MRI abnormalities affecting the commissures, corpus callosum, pineal gland; cataracts; glaucoma (Williamson et al., 2019 (PMID 31700164); Abouzeid et al. 2009 (PMID 19862335). Glaser et al. 1994; PMID 7951315: A proband with compound heterozygous nonsense variants, c.607C>T (p.Arg203Ter) and c.1058C>G (p.Ser353Ter), presented with anophthalmia, microcephaly, complete agenesis of the corpus callosum and olfactory bulbs, hypoplasia of the cerebellum and pons, and died in the neonatal period. Solomon et al., 2010 (PMID 19876904): A surviving patient with compound heterozygous mutations in PAX6 presented with microphthalmia, neonatal diabetes mellitus, hypopituitarism, and microcephaly, as well as trisomy 21. The patient inherited a missense mutation affecting the paired domain from the father (c.112C>T, p.Arg38Trp), who had microcornea and severe cataracts, and a nonsense mutation in HD from the mother (c.718C>T, p.Arg240Ter), who presented with classical familial aniridia. Complex brain anomalies including absent corpus callosum, hypoplastic brainstem, near-absent olfactory bulbs, and polymicrogyria were noted. Schmidt-Sidor et al., 2009 (PMID 20054790) described a stillborn fetus; PAX6 c.117_128del12 (affecting the paired domain) and a frameshift variant, c.112delC, were identified in compound heterozygosity; autopsy revealed major CNS abnormalities including complete agenesis of the corpus callosum, cortical malformations and various cerebellar anomalies including cerebellar dysplasia; a similar phenotype was observed in a subsequent pregnancy. This severe CNS malformation phenotype is recapitulated in the Sey (Small eye) mouse, which carries a PAX6 LoF point mutation c.622G>T (p.Gly208Ter) (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)); Pax6 is produced in cerebellar granule cells and that PAX6 influences the morphogenesis of the whole cerebellum; homozygous Pax6Sey/Sey mice exhibit severe brain malformations, including cerebellar abnormalities, and die perinatally, whereas heterozygous Pax6Sey/+ mice survive and show developmental defects consistent with PAX6 haploinsufficiency. 3 unrelated patients are reported and the biallelic Sey mouse model recapitulates the human phenotype, thus a green rating for biallelic inheritance is recommended. It is unclear whether monoallelic PAX6-related disease lies within the intended scope of the fetal anomalies panel, thus expert review is requested for monoallelic PAX6-related disease. |
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| Limb disorders v9.6 | LRP4 |
Ida Ertmanska changed review comment from: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails. Complications included such as dizziness, difficulties with gait and coordination, vertigo, and spastic and ataxic gait disturbances. Several neurological complications, such as facial nerve palsy and hearing loss, were present due to bone compression of cranial nerves. X-rays revealed severe thickening of the calvaria and the cortices of the long bones. Diagnosed with sclerosteosis. Her parents were reported to be unaffected. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant.; to: MONOALLELIC CASES: PMID: 37563890 Khan et al., 2023 Report of a Pakistani family with dominantly segregating polydactyly, and phalangeal synostosis. WES in the proband identified a heterozygous variant in LRP4: c.G1696A, p.(Gly566Ser) - 5 hets reported in gnomAD v4 (European pop). Good variant segregation with phenotype shown by Sanger sequencing of 3 affected and 2 unaffected individuals. PMID: 21471202 Leupin et al., 2011 Identified two mutations in LRP4 (R1170W and W1186S) in patients with bone overgrowth P1 = 45yo female of Greek origin (previously described in PMID: 11385236). She had syndactyly of the fingers with hypoplasia of the second finger on both hands as well as dysplastic nails. Complications included such as dizziness, difficulties with gait and coordination, vertigo, and spastic and ataxic gait disturbances. Several neurological complications, such as facial nerve palsy and hearing loss, were present due to bone compression of cranial nerves. X-rays revealed severe thickening of the calvaria and the cortices of the long bones. Diagnosed with sclerosteosis. Her parents were reported to be unaffected - not genotyped. Homozygous for LRP4 c.3508C>T, p.Arg1170Trp. 5 hets reported in gnomAD v4.1.2. P2 = Spanish male (previously described in PMID: 7891385) with syndactyly and shortening of several phalanges in his hands as well as mild facial nerve palsy. X-rays revealed a sclerotic calvaria and a very dense base of the skull; all long bones were showing cortical hyperostosis. Diagnosed with sclerosteosis. Parents unaffected. Heterozygous for LRP4 c.3557G>C, p.Trp1186Ser (confirmed de novo, did not segregate to his children). 10 hets reported in gnomAD v4 for this variant. |
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| Limb disorders v9.6 | LRP4 | Ida Ertmanska reviewed gene: LRP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21471202, 37563890; Phenotypes: Cenani-Lenz syndactyly syndrome, OMIM:212780, Sclerosteosis 2, OMIM:614305; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.35 | PAX6 | Luke Stuart edited their review of gene: PAX6: Changed publications to: 17148041, 8188215, 7951315, 20054790, 19876904, 17417613, 8213068, 16979618, 19876904 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.35 | PAX6 |
Luke Stuart changed review comment from: Early literature suspected PAX6 as the causative gene for Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation), but direct sequencing repeatedly found no PAX6 mutations in classic Gillespie cases. Linkage analysis in affected families showed the disease trait segregates independently from chromosome 11p markers flanking PAX6 (Glaser et al., 1994; PMID 8188215). The causative gene was identified as ITPR1. PAX6 biallelic loss-of-function causes a severe, prenatal/neonatal-onset neurodevelopmental disorder characterised by anophthalmia/microphthalmia and major CNS malformations, including agenesis of the corpus callosum, olfactory bulb aplasia/hypoplasia, brainstem hypoplasia, cortical malformations, and cerebellar dysplasia/hypoplasia; reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities (Glaser et al., 1994, PMID: 7951315; Schmidt-Sidor et al., 2009, PMID: 20054790; Solomon et al., 2010, PMID: 19876904). Thus, biallelic PAX6-related disease is not within scope for the paediatric onset ataxia/ cerebellar anomalies panels. Isolated reports describe heterozygous PAX6 variants associated with neurological manifestations, including ataxia or cerebellar dysfunction: Ticho et al., 2006 (PMID: 17148041): A patient described as having "atypical Gillespie syndrome" presented with mild hand tremor and learning disability but no reported ataxia or structural cerebellar abnormalities on neuroimaging. Sequencing identified a heterozygous PAX6 splice-site variant, IVS2+2T>A. Graziano et al., 2007 (PMID 17595013): described a 9.5-year-old girl with bilateral aniridia, ataxia, and intellectual disability; she carried a de novo heterozygous nonsense variant, PAX6 p.(Trp257Ter). Dansault et al., 2007 (PMID 17417613): In a large family carrying the c.655A>G p.S74G variant, all affected individuals exhibited a mild but consistent cerebellar syndrome. The most severely affected individual had a clear static cerebellar syndrome. MRI findings included hypoplasia of the anterior commissure and absence of the pineal gland in one individual. Despite the consistent neurological phenotype, no specific structural cerebellar abnormalities were identified. Conclusion: Two unrelated PAX6 families with heterozygous variants showed evidence ataxia and/or a cerebellar syndrome phenotype, the latter without any recognisable cerebellar malformation. PAX6 knockout mice delineate a primary role of PAX6 in cerebellar development, though are not known to recapitulate an ataxia phenotype, nor cerebellar phenotype in the context of haploinsufficiency (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)). An amber rating with monoallelic inheritance is proposed.; to: Early literature suspected PAX6 as the causative gene for Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation), but direct sequencing repeatedly found no PAX6 mutations in classic Gillespie cases. Linkage analysis in affected families showed the disease trait segregates independently from chromosome 11p markers flanking PAX6 (Glaser et al., 1994; PMID 8188215). The causative gene was identified as ITPR1. PAX6 biallelic loss-of-function causes a severe, prenatal/neonatal-onset neurodevelopmental disorder characterised by anophthalmia/microphthalmia and major CNS malformations, including agenesis of the corpus callosum, olfactory bulb aplasia/hypoplasia, brainstem hypoplasia, cortical malformations, and cerebellar dysplasia/hypoplasia; reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities (Glaser et al., 1994, PMID: 7951315; Schmidt-Sidor et al., 2009, PMID: 20054790; Solomon et al., 2010, PMID: 19876904). A rare paediatric report described a 4-year-old proband with compound heterozygous PAX6 variants (1x missense affecting the paired domain and 1x nonsense); they presented with structural brain anomalies including agenesis of the corpus callosum, hypoplastic pons and vermis (absent inferiorly), possible Dandy-Walker malformation, pituitary and hypothalamic hypoplasia; attribution of these phenotypic features to PAX6 is confounded by the proband's dual diagnosis including trisomy 21 (Solomon et al., 2009 (PMID 19876904). Isolated reports describe heterozygous PAX6 variants associated with neurological manifestations, including ataxia or cerebellar dysfunction: Ticho et al., 2006 (PMID: 17148041): A patient described as having "atypical Gillespie syndrome" presented with mild hand tremor and learning disability but no reported ataxia or structural cerebellar abnormalities on neuroimaging. Sequencing identified a heterozygous PAX6 splice-site variant, IVS2+2T>A. Graziano et al., 2007 (PMID 17595013): described a 9.5-year-old girl with bilateral aniridia, ataxia, and intellectual disability; she carried a de novo heterozygous nonsense variant, PAX6 p.(Trp257Ter). Dansault et al., 2007 (PMID 17417613): In a large family carrying the c.655A>G p.S74G variant, all affected individuals exhibited a mild but consistent cerebellar syndrome. The most severely affected individual had a clear static cerebellar syndrome. MRI findings included hypoplasia of the anterior commissure and absence of the pineal gland in one individual. Despite the consistent neurological phenotype, no specific structural cerebellar abnormalities were identified. Conclusion: Two unrelated PAX6 families with heterozygous variants showed evidence ataxia and/or a cerebellar syndrome phenotype, the latter without any recognisable cerebellar malformation. PAX6 knockout mice delineate a primary role of PAX6 in cerebellar development, though are not known to recapitulate an ataxia phenotype, nor cerebellar phenotype in the context of haploinsufficiency (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)). An amber rating with monoallelic inheritance is proposed. |
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| Neurodegenerative disorders, adult onset v9.25 | ARSA | Achchuthan Shanmugasundram Phenotypes for gene: ARSA were changed from Metachromatic leukodystrophy, OMIM:250100; Dystonia to Metachromatic leukodystrophy, OMIM:250100; metachromatic leukodystrophy, MONDO:0018868; arylsulfatase A deficiency | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.24 | ARSA | Achchuthan Shanmugasundram Publications for gene: ARSA were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.12 | PSAP |
Ida Ertmanska Tag Q3_26_expert_review was removed from gene: PSAP. Tag Q3_26_demote_red was removed from gene: PSAP. |
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| Retinal disorders v9.19 | IDUA |
Siying Lin gene: IDUA was added gene: IDUA was added to Retinal disorders. Sources: Literature Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IDUA were set to 42838055 Phenotypes for gene: IDUA were set to Retinitis pigmentosa; atteunated MPS I Mode of pathogenicity for gene: IDUA was set to Other Review for gene: IDUA was set to GREEN Added comment: Biallelic hypomorphic IDUA variants have been shown to cause late-onset retinal-predominant disease, including apparently non-syndromic retinitis pigmentosa, in a multi-centre cohort of 14 affected individuals from 12 unrelated families, supported by functional and biochemical validation. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | ZNF699 | Isaac Machado Azevedo reviewed gene: ZNF699: Rating: AMBER; Mode of pathogenicity: ; Publications: 42534679; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | SLC35A1 | Isaac Machado Azevedo reviewed gene: SLC35A1: Rating: AMBER; Mode of pathogenicity: ; Publications: 28856833, 40613041, 15576474, 30115659, 23873973; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | DDX58 | Isaac Machado Azevedo reviewed gene: DDX58: Rating: AMBER; Mode of pathogenicity: ; Publications: 33495304, 25620203, 30574673, 41467011; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | PTPN1 | Isaac Machado Azevedo reviewed gene: PTPN1: Rating: AMBER; Mode of pathogenicity: ; Publications: 39986310, 41959779 (preprint, medRxiv); Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | MPL | Isaac Machado Azevedo reviewed gene: MPL: Rating: AMBER; Mode of pathogenicity: ; Publications: 32703794, 10077649, 10971406, 18090929; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | MAP2K1 | Isaac Machado Azevedo reviewed gene: MAP2K1: Rating: AMBER; Mode of pathogenicity: ; Publications: 36054331, 40692796, 36313893, 32866538; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | GALE | Isaac Machado Azevedo reviewed gene: GALE: Rating: AMBER; Mode of pathogenicity: ; Publications: 34159722, 36395340, 36056436, 41986803; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | DSG1 | Isaac Machado Azevedo reviewed gene: DSG1: Rating: AMBER; Mode of pathogenicity: ; Publications: 25041099, 27154412, 23974871, 27632246, 26288349; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | DGAT1 | Isaac Machado Azevedo reviewed gene: DGAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: 26883093, 29604290, 23114594, 40154740; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | BRAF | Isaac Machado Azevedo reviewed gene: BRAF: Rating: AMBER; Mode of pathogenicity: ; Publications: 40692796, 39372827, 36938251; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | TKFC | Isaac Machado Azevedo reviewed gene: TKFC: Rating: AMBER; Mode of pathogenicity: ; Publications: 38697782; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | ASXL1 | Isaac Machado Azevedo reviewed gene: ASXL1: Rating: AMBER; Mode of pathogenicity: ; Publications: 40742536; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | RGS10 | Isaac Machado Azevedo reviewed gene: RGS10: Rating: AMBER; Mode of pathogenicity: ; Publications: 34315806; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | CASP1 | Isaac Machado Azevedo reviewed gene: CASP1: Rating: AMBER; Mode of pathogenicity: ; Publications: 32556329; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | CARD10 | Isaac Machado Azevedo reviewed gene: CARD10: Rating: AMBER; Mode of pathogenicity: ; Publications: 32238915; Phenotypes: Immunodeficiency 89 and autoimmunity (IMD89) (MONDO:0030484); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | PSMA3 | Isaac Machado Azevedo reviewed gene: PSMA3: Rating: AMBER; Mode of pathogenicity: ; Publications: 37600812, 26524591; Phenotypes: Proteasome-associated autoinflammatory syndrome 1 (PRAAS1, CANDLE) (MONDO:0054698); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | FGR | Isaac Machado Azevedo reviewed gene: FGR: Rating: AMBER; Mode of pathogenicity: ; Publications: 41920357; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | IRAK2 | Isaac Machado Azevedo reviewed gene: IRAK2: Rating: AMBER; Mode of pathogenicity: ; Publications: 39299377, 42168171; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | CLEC7A | Isaac Machado Azevedo reviewed gene: CLEC7A: Rating: AMBER; Mode of pathogenicity: ; Publications: 31613800, 36377664, 19864674; Phenotypes: Candidiasis, familial, 4 (CANDF4) (MONDO:0013140); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | PLD4 | Isaac Machado Azevedo reviewed gene: PLD4: Rating: AMBER; Mode of pathogenicity: ; Publications: 41073790, 40931063, 25052073; Phenotypes: Systemic lupus erythematosus 18 (SLE18) (MONDO:1060185); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | IVNS1ABP | Isaac Machado Azevedo reviewed gene: IVNS1ABP: Rating: AMBER; Mode of pathogenicity: ; Publications: 32499645; Phenotypes: Immunodeficiency 70 (IMD70) (MONDO:0033542); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | RC3H1 | Isaac Machado Azevedo reviewed gene: RC3H1: Rating: AMBER; Mode of pathogenicity: ; Publications: 31636267, 40769319; Phenotypes: Immune dysregulation and systemic hyperinflammation syndrome (IMDYSHI) (MONDO:0033557); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | CD48 | Isaac Machado Azevedo reviewed gene: CD48: Rating: AMBER; Mode of pathogenicity: ; Publications: 41984595, 31419545; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | LRRC8A | Isaac Machado Azevedo reviewed gene: LRRC8A: Rating: AMBER; Mode of pathogenicity: ; Publications: 14660746; Phenotypes: Agammaglobulinemia 5, autosomal dominant (AGM5) (MONDO:0013290); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | SH3GL1 | Isaac Machado Azevedo reviewed gene: SH3GL1: Rating: AMBER; Mode of pathogenicity: ; Publications: 34323351, 39499372; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | SIT1 | Isaac Machado Azevedo reviewed gene: SIT1: Rating: AMBER; Mode of pathogenicity: ; Publications: 42128181; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | CSF3 | Isaac Machado Azevedo reviewed gene: CSF3: Rating: AMBER; Mode of pathogenicity: ; Publications: 37612131, 42358053; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | SAT1 | Isaac Machado Azevedo reviewed gene: SAT1: Rating: AMBER; Mode of pathogenicity: ; Publications: 35977808; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | DNAJC17 | Isaac Machado Azevedo reviewed gene: DNAJC17: Rating: AMBER; Mode of pathogenicity: ; Publications: 42495638; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | ZNF699 |
Achchuthan Shanmugasundram gene: ZNF699 was added gene: ZNF699 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | SLC35A1 |
Achchuthan Shanmugasundram gene: SLC35A1 was added gene: SLC35A1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: SLC35A1 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | DDX58 |
Achchuthan Shanmugasundram gene: DDX58 was added gene: DDX58 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: DDX58 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | PTPN1 |
Achchuthan Shanmugasundram gene: PTPN1 was added gene: PTPN1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | MPL |
Achchuthan Shanmugasundram gene: MPL was added gene: MPL was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: MPL was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | MAP2K1 |
Achchuthan Shanmugasundram gene: MAP2K1 was added gene: MAP2K1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: MAP2K1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | GALE |
Achchuthan Shanmugasundram gene: GALE was added gene: GALE was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: GALE was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | DSG1 |
Achchuthan Shanmugasundram gene: DSG1 was added gene: DSG1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: DSG1 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | DGAT1 |
Achchuthan Shanmugasundram gene: DGAT1 was added gene: DGAT1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: DGAT1 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | BRAF |
Achchuthan Shanmugasundram gene: BRAF was added gene: BRAF was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: BRAF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | TKFC |
Achchuthan Shanmugasundram gene: TKFC was added gene: TKFC was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | CASP1 |
Achchuthan Shanmugasundram gene: CASP1 was added gene: CASP1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: CASP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | IRAK2 |
Achchuthan Shanmugasundram gene: IRAK2 was added gene: IRAK2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: IRAK2 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | CLEC7A |
Achchuthan Shanmugasundram gene: CLEC7A was added gene: CLEC7A was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: CLEC7A was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | PLD4 |
Achchuthan Shanmugasundram gene: PLD4 was added gene: PLD4 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: PLD4 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | SH3GL1 |
Achchuthan Shanmugasundram gene: SH3GL1 was added gene: SH3GL1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: SH3GL1 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | CSF3 |
Achchuthan Shanmugasundram gene: CSF3 was added gene: CSF3 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: CSF3 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | SAT1 |
Achchuthan Shanmugasundram gene: SAT1 was added gene: SAT1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: SAT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.108 | DNAJC17 |
Achchuthan Shanmugasundram gene: DNAJC17 was added gene: DNAJC17 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: DNAJC17 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Neurodegenerative disorders, adult onset v9.23 | MME | Luke Stuart reviewed gene: MME: Rating: AMBER; Mode of pathogenicity: None; Publications: 31429185; Phenotypes: ?Spinocerebellar ataxia 43 (OMIM:617018), Charcot-Marie-Tooth disease, axonal, type 2T (OMIM:617017); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.38 | FIG4 | Achchuthan Shanmugasundram Publications for gene: FIG4 were set to 17572665; 19118816; 23888880; 21705420 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.23 | DYNC1H1 | Luke Stuart reviewed gene: DYNC1H1: Rating: AMBER; Mode of pathogenicity: None; Publications: 38848546; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2O (OMIM:614228), Spinal muscular atrophy, lower extremity-predominant 1 (OMIM:158600); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.23 | IGHMBP2 | Ida Ertmanska Mode of inheritance for gene: IGHMBP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.37 | FIG4 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: FIG4. Tag Q3_26_MOI tag was added to gene: FIG4. |
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| Hereditary neuropathy or pain disorder v8.37 | FIG4 | Ida Ertmanska commented on gene: FIG4: Comment on mode of inheritance: There is some evidence for the association between FIG4 and dominant Amyotrophic lateral sclerosis. While multiple cases have been reported, there is no convincing segregation data, or functional evidence to support a dominant disease mechanism. Hence, the mode of inheritance should be changed from 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' to 'BIALLELIC, autosomal or pseudoautosomal'. An expert_review tag was added to ensure GMS agreement on the strength of evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.37 | FIG4 |
Ida Ertmanska changed review comment from: FIG4 ALS-related reports: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022). 2021 review by Ian Berry on the Neurodegenerative disorders, adult onset panel: "Association of FIG4 with ALS remains in question. Main evidence is from Chow 2009 paper PMID: 19118816 where 5 proven deleterious variants were identified in a 473 patient cohort. There are 666 rare (<5 instances) protein altering & splice donor/acceptor variants in gnomAD v.2.1 https://gnomad.broadinstitute.org/gene/ENSG00000112367?dataset=gnomad_r2_1, with a denominator of ~125,000 patients. Other studies of FIG4 in ALS cohorts are under-powered to show a clear enrichment of proven deleterious alleles. Using Pearson's Chi-squared test these two cohorts do not have a significant difference in rare/deleterious variant rate at p.<0.05. I haven't seen any convincing segregation evidence for a FIG4 variant in a large ALS family, and am unaware of any functional studies or animal models showing a convincing genotype-phenotype association. I do not think this gene (yet) clearly satisfies the threshold of probability for a dominant cause of ALS."; to: FIG4 ALS-related reports: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 - biallelic ALS case Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022). 2021 review by Ian Berry on the Neurodegenerative disorders, adult onset panel: "Association of FIG4 with ALS remains in question. Main evidence is from Chow 2009 paper PMID: 19118816 where 5 proven deleterious variants were identified in a 473 patient cohort. There are 666 rare (<5 instances) protein altering & splice donor/acceptor variants in gnomAD v.2.1 https://gnomad.broadinstitute.org/gene/ENSG00000112367?dataset=gnomad_r2_1, with a denominator of ~125,000 patients. Other studies of FIG4 in ALS cohorts are under-powered to show a clear enrichment of proven deleterious alleles. Using Pearson's Chi-squared test these two cohorts do not have a significant difference in rare/deleterious variant rate at p.<0.05. I haven't seen any convincing segregation evidence for a FIG4 variant in a large ALS family, and am unaware of any functional studies or animal models showing a convincing genotype-phenotype association. I do not think this gene (yet) clearly satisfies the threshold of probability for a dominant cause of ALS." |
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| Hereditary neuropathy or pain disorder v8.37 | FIG4 |
Ida Ertmanska changed review comment from: FIG4 ALS-related reports: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).; to: FIG4 ALS-related reports: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022). 2021 review by Ian Berry on the Neurodegenerative disorders, adult onset panel: "Association of FIG4 with ALS remains in question. Main evidence is from Chow 2009 paper PMID: 19118816 where 5 proven deleterious variants were identified in a 473 patient cohort. There are 666 rare (<5 instances) protein altering & splice donor/acceptor variants in gnomAD v.2.1 https://gnomad.broadinstitute.org/gene/ENSG00000112367?dataset=gnomad_r2_1, with a denominator of ~125,000 patients. Other studies of FIG4 in ALS cohorts are under-powered to show a clear enrichment of proven deleterious alleles. Using Pearson's Chi-squared test these two cohorts do not have a significant difference in rare/deleterious variant rate at p.<0.05. I haven't seen any convincing segregation evidence for a FIG4 variant in a large ALS family, and am unaware of any functional studies or animal models showing a convincing genotype-phenotype association. I do not think this gene (yet) clearly satisfies the threshold of probability for a dominant cause of ALS." |
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| Hereditary neuropathy or pain disorder v8.37 | FIG4 |
Ida Ertmanska changed review comment from: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).; to: FIG4 ALS-related reports: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022). |
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| Neurodegenerative disorders, adult onset v9.22 | FIG4 | Ida Ertmanska edited their review of gene: FIG4: Changed phenotypes to: Amyotrophic lateral sclerosis 11, OMIM:612577, amyotrophic lateral sclerosis type 11, MONDO:0012945 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.37 | FIG4 | Ida Ertmanska reviewed gene: FIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28051077, 29464931, 35021275, 36090855, 38695966; Phenotypes: Amyotrophic lateral sclerosis 11, OMIM:612577, amyotrophic lateral sclerosis type 11, MONDO:0012945; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | FIG4 | Ida Ertmanska edited their review of gene: FIG4: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | IGHMBP2 | Luke Stuart reviewed gene: IGHMBP2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2S (OMIM:616155), Neuronopathy, distal hereditary motor, autosomal recessive 1 (OMIM:604320); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal ciliopathies v5.2 | C2CD3 |
Aakash Joshi gene: C2CD3 was added gene: C2CD3 was added to Renal ciliopathies. Sources: Literature Mode of inheritance for gene: C2CD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C2CD3 were set to PMCID 11811416 Phenotypes for gene: C2CD3 were set to renal cysts; multisystem ciliopathy; renal ciliopathy Penetrance for gene: C2CD3 were set to Complete Review for gene: C2CD3 was set to GREEN Added comment: PMCID 11811416 identified 1 individual with biallelic variants in C2CD3 with isolated nephronophthisis. C2CD3 is associated with Orofaciodigitial syndrome 14, which is a known multisystem ciliopathy (OMIM 615948), with renal features reported including renal cysts. Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.22 | SORD | Luke Stuart reviewed gene: SORD: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 8 (OMIM:618912), neuronopathy, distal hereditary motor, autosomal recessive 8 (MONDO:0030055); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | SYT2 | Luke Stuart reviewed gene: SYT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26519543, 30533528; Phenotypes: Myasthenic syndrome, congenital, 7A, presynaptic, and distal motor neuropathy, autosomal dominant (OMIM:616040); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | HSPB1 | Eleanor Williams commented on gene: HSPB1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal ciliopathies v5.2 | ZNF423 | Aakash Joshi reviewed gene: ZNF423: Rating: AMBER; Mode of pathogenicity: None; Publications: PMCID 11282974; Phenotypes: cystic renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | SLC5A7 | Luke Stuart edited their review of gene: SLC5A7: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | SLC5A7 | Luke Stuart reviewed gene: SLC5A7: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant 7 (OMIM:158580); Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | TRPV4 | Luke Stuart reviewed gene: TRPV4: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant 8 (OMIM:600175), Hereditary motor and sensory neuropathy, type IIc (OMIM:606071), Scapuloperoneal spinal muscular atrophy (OMIM:181405); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.87 | CSNK1A1 |
Alexandra Njegic gene: CSNK1A1 was added gene: CSNK1A1 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: CSNK1A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CSNK1A1 were set to 40156289 Phenotypes for gene: CSNK1A1 were set to Infantile spasms syndrome Penetrance for gene: CSNK1A1 were set to unknown Review for gene: CSNK1A1 was set to AMBER Added comment: PMID: 40156289 describes 2 unrelated families with de novo variants in CSNK1A1 (proband 1 harboured a small del variant, proband 2 harboured a missense variant, both were shown to have early-onset epileptic encephalopathy); confirmed variant on Sanger (obtained from WES). Mechanism of disease proposed to be due to reduced interactions between CSNK1A1 and β-catenin in variant CSNK1A1, resulting in excessive intracellular β-catenin and aberrant expression of several downstream genes. Only 2 families reported in the literature. Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.22 | PLEKHG5 | Luke Stuart reviewed gene: PLEKHG5: Rating: AMBER; Mode of pathogenicity: None; Publications: 17564964, 33275839; Phenotypes: Charcot-Marie-Tooth disease, recessive intermediate C (OMIM:615376, Neuronopathy, distal hereditary motor, autosomal recessive 4 (OMIM:611067); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | SIGMAR1 |
Achchuthan Shanmugasundram Tag Q3_26_expert_review was removed from gene: SIGMAR1. Tag Q3_26_NHS_review was removed from gene: SIGMAR1. Tag Q3_26_promote_green was removed from gene: SIGMAR1. |
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| Neurodegenerative disorders, adult onset v9.22 | SIGMAR1 | Achchuthan Shanmugasundram Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | SIGMAR1 | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | HSPB8 |
Luke Stuart changed review comment from: As reviewed by Oliver Ziff, HSPB8-related disease may present in adulthood or enter an adult lower motor neuron (LMN) disease or progressive muscular atrophy (PMA) diagnostic pathway because of overlapping clinical presentation (Putko et al. (2025) PMID 41426051)). NHS England review is ongoing to determine whether HSPB8 falls within the intended scope of the adult-onset neurodegenerative disorders panel, based on potential diagnostic utility rather than a definitive association with adult-onset neurodegeneration.; to: HSPB8 is associated with Charcot-Marie-Tooth disease, axonal, type 2L (OMIM:608673); Myopathy, myofibrillar, 13, with rimmed vacuoles (OMIM:621078); Neuronopathy, distal hereditary motor, autosomal dominant 2 (OMIM:158590) (accessed 10/2026). As reviewed by Oliver Ziff, HSPB8-related disease may present in adulthood or enter an adult lower motor neuron (LMN) disease or progressive muscular atrophy (PMA) diagnostic pathway because of overlapping clinical presentation (Putko et al. (2025) PMID 41426051)). NHS England review is ongoing to determine whether HSPB8 falls within the intended scope of the adult-onset neurodegenerative disorders panel, based on potential diagnostic utility rather than a definitive association with adult-onset neurodegeneration. |
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| Neurodegenerative disorders, adult onset v9.22 | HSPB8 | Luke Stuart reviewed gene: HSPB8: Rating: AMBER; Mode of pathogenicity: None; Publications: 41426051; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2L (OMIM:608673), Myopathy, myofibrillar, 13, with rimmed vacuoles (OMIM:621078), Neuronopathy, distal hereditary motor, autosomal dominant 2 (OMIM:158590), neuronopathy, distal hereditary motor, type 2A (MONDO:0008025), Charcot-Marie-Tooth disease axonal type 2L (MONDO:0012096); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | HSPB1 |
Luke Stuart changed review comment from: Variants in HSPB1 are a recurrent and established cause of distal Hereditary Motor Neuropathy (dHMN), and are associated with Charcot-Marie-Tooth disease, axonal, type 2F (CMT2F, OMIM:606595) and Neuronopathy, distal hereditary motor, autosomal dominant 3 (OMIM:608634) (accessed 10/2026). In a cohort of 301 individuals with CMT and 115 with distal hereditary motor neuropathy, a segregating HSPB1 missense variant was identified in a Russian CMT2F family, with four additional missense variants found across four distal-HMN families; mutant HSPB1 reduced neuronal-cell viability and disrupted neurofilament assembly (Evgrafov et al., (2004), PMID 15122254). As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease- in a natural history study of HSBP1 neuropathy, patients developed adult-onset progressive weakness, wasting and chronic denervation (Rossor et al. (2016), PMID 27816334. Evidence for a direct association with classical ALS is limited and equivocal: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as a potential risk modifier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection. Expert review is recommended to determine whether HSPB1 should be included in the adult onset neurodegenerative disorders panel to capture patients with HSPB1-related neuropathy who clinically mimic progressive muscular atrophy or motor neuron disease, rather than as an established cause of motor neuron disease.; to: Variants in HSPB1 are a recurrent and established cause of distal Hereditary Motor Neuropathy (dHMN), and are associated with Charcot-Marie-Tooth disease, axonal, type 2F (CMT2F, OMIM:606595) and Neuronopathy, distal hereditary motor, autosomal dominant 3 (OMIM:608634) (accessed 10/2026). In a cohort of 301 individuals with CMT and 115 with distal hereditary motor neuropathy, a segregating HSPB1 missense variant was identified in a Russian CMT2F family, with four additional missense variants found across four distal-HMN families; mutant HSPB1 reduced neuronal-cell viability and disrupted neurofilament assembly (Evgrafov et al., (2004), PMID 15122254). As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease- in a natural history study of HSBP1 neuropathy, patients developed adult-onset progressive weakness, wasting and chronic denervation (Rossor et al. (2016), PMID 27816334. Evidence for a direct association with classical ALS is limited and equivocal: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as a potential risk modifier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection. NHS England review is ongoing to determine whether HSPB1 should be included in the adult onset neurodegenerative disorders panel to capture patients with HSPB1-related neuropathy who clinically mimic progressive muscular atrophy or motor neuron disease, rather than as an established cause of motor neuron disease. |
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| Neurodegenerative disorders, adult onset v9.22 | SIGMAR1 |
Luke Stuart changed review comment from: SIGMAR1 is provisionally associated with autosomal recessive Amyotrophic lateral sclerosis 16, juvenile (OMIM:614373) and Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726) (accessed 10/2026). Multiple patients with biallelic variants have been identified, and disease onset is typically in the first decade (Kalita et al. (2025), PMID 41334667; Al-Saif et al. (2011), PMID 21842496, Horga et al. (2016) PMID 27629094). Disruption of Sigmar1 in the mouse leads to locomotor deficit (Bernard-Marissal et al. (2015), PMID 25678561). Biallelic SIGMAR1 variants typically cause a phenotypic spectrum encompassing juvenile ALS16 and distal hereditary motor neuropathy with pyramidal signs. Recent evidence supports a spectrum of SIGMAR1-related motor neuropathy, with the slowly progressive, distal-predominant phenotype generally favouring dHMN over classical ALS (Yu et al. (2025), PMID 40309037; Kalita et al. (2025), PMID 41334667)). Adult presentation is documented in isolated cases. Ma et al. (2020), PMID 32600828 reported onset at 34 years in a patient with compound-heterozygous c.247T>C and c.545T>C variants who was referred to an ALS clinic with distal weakness and hyperreflexia; the authors classified the phenotype as dHMN mimicking ALS. An additional Japanese patient developed ALS at 80 years with compound-heterozygous missense variants, though notably, one of the variants (p.R208W) has an allele frequency of 2.9% in East Asians via gnomad v4 and 64 homozygotes across all populations (Izumi et al. (2018), PMID 30311446). Evidence implicating SIGMAR1 in typical adult-onset ALS or ALS–FTD remains disputed (Pickering-Brown et al. (2015), PMID 26088964). SIGMAR1 c.672*51G>T was identified in 3 families with ALS-FTD, though later studies found one of the families also to harbored a C9ORF72 expansion (Luty et al. (2010), PMID 21031579. As reviewed by Oliver Ziff, despite typical childhood onset, SIGMAR1-related disease can thus present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. Expert review is therefore warranted to determine whether SIGMAR1 should be included on the adult-onset neurodegenerative disorders panel in the context of diagnostic utility, rather than in relation to a definitive association between SIGMAR1 and adult-onset neurodegeneration.; to: SIGMAR1 is provisionally associated with autosomal recessive Amyotrophic lateral sclerosis 16, juvenile (OMIM:614373) and Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726) (accessed 10/2026). Multiple patients with biallelic variants have been identified, and disease onset is typically in the first decade (Kalita et al. (2025), PMID 41334667; Al-Saif et al. (2011), PMID 21842496, Horga et al. (2016) PMID 27629094). Disruption of Sigmar1 in the mouse leads to locomotor deficit (Bernard-Marissal et al. (2015), PMID 25678561). Biallelic SIGMAR1 variants typically cause a phenotypic spectrum encompassing juvenile ALS16 and distal hereditary motor neuropathy with pyramidal signs. Recent evidence supports a spectrum of SIGMAR1-related motor neuropathy, with the slowly progressive, distal-predominant phenotype generally favouring dHMN over classical ALS (Yu et al. (2025), PMID 40309037; Kalita et al. (2025), PMID 41334667)). Adult presentation is documented in isolated cases. Ma et al. (2020), PMID 32600828 reported onset at 34 years in a patient with compound-heterozygous c.247T>C and c.545T>C variants who was referred to an ALS clinic with distal weakness and hyperreflexia; the authors classified the phenotype as dHMN mimicking ALS. An additional Japanese patient developed ALS at 80 years with compound-heterozygous missense variants, though notably, one of the variants (p.R208W) has an allele frequency of 2.9% in East Asians via gnomad v4 and 64 homozygotes across all populations (Izumi et al. (2018), PMID 30311446). Evidence implicating SIGMAR1 in typical adult-onset ALS or ALS–FTD remains disputed (Pickering-Brown et al. (2015), PMID 26088964). SIGMAR1 c.672*51G>T was identified in 3 families with ALS-FTD, though later studies found one of the families also to harbored a C9ORF72 expansion (Luty et al. (2010), PMID 21031579. As reviewed by Oliver Ziff, despite typical childhood onset, SIGMAR1-related disease can thus present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. NHS England review is ongoing to determine whether SIGMAR1 falls within the intended scope of the adult-onset neurodegenerative disorders panel, based on potential diagnostic utility rather than a definitive association with adult-onset neurodegeneration. |
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| Severe microcephaly v9.34 | CRIPT | Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CRIPT. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.34 | CRIPT | Ida Ertmanska changed review comment from: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with microcephalic dwarfism being a consistent feature. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with microcephalic dwarfism being a consistent feature. 5/6 probands had microcephaly reported, though the severity only reached -2.5 to -2.7 SD in 3 of these cases. Hence, this gene can be promoted to Green at the next update, with an expert_review tag added to ensure that consistent near-severe microcephaly is in scope of this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.13 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients. P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees. P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification. F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature; to: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients. P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees. P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. "Patient had not been evaluated for his mild anemia." PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification. F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature |
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| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. A similar decision was made for TBX6 inclusion on Skeletal dysplasia, based on a common hypomorphic risk haplotype. An expert-review tag was added to ensure GMS agreement regarding inclusion of cases with the common HSPA9 variant. ; to: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. A similar decision was made for TBX6 inclusion on Skeletal dysplasia, based on a common hypomorphic risk haplotype reported in trans with a rare variant. An expert-review tag was added to ensure GMS agreement regarding inclusion of cases with the common HSPA9 variant. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. An expert-review tag was added to ensure GMS agreement regarding inclusion of cases with the common HSPA9 variant.; to: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. A similar decision was made for TBX6 inclusion on Skeletal dysplasia, based on a common hypomorphic risk haplotype. An expert-review tag was added to ensure GMS agreement regarding inclusion of cases with the common HSPA9 variant. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. An expert-review tag was added to ensure GMS agreement regarding inclusion of cases with the common HSPA9 variant. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: HSPA9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.11 | SMOC2 | Ida Ertmanska Classified gene: SMOC2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.11 | SMOC2 | Ida Ertmanska Added comment: Comment on list classification: There are multiple probands reported in literature with biallelic SMOC2 variants and dentin dysplasia, with teeth abnormalities including oligodontia and abnormal tooth shape. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.11 | SMOC2 | Ida Ertmanska Gene: smoc2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.10 | SMOC2 |
Ida Ertmanska gene: SMOC2 was added gene: SMOC2 was added to Ectodermal dysplasia. Sources: Literature Q3_26_promote_green tags were added to gene: SMOC2. Mode of inheritance for gene: SMOC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SMOC2 were set to 22152679; 23317772; 32908163 Phenotypes for gene: SMOC2 were set to Dentin dysplasia, type IA, OMIM:125400; atypical dentin dysplasia due to SMOC2 deficiency, MONDO:0017819; dentin dysplasia type 1 with microdontia and shape anomalies Review for gene: SMOC2 was set to GREEN Added comment: PMID: 22152679 Bloch-Zupan et al., 2011 Report of a severe developmental dental defect that results in a dentin dysplasia phenotype with major microdontia, oligodontia, and shape abnormalities in a highly consanguineous family. 2 affected children were found to carry a homozygous mutation in SMOC2: c.84+1G>T. Unaffected sibs were heterozygous for the variant. Method: Homozygosity mapping, WES, direct sequencing - SMOC2 was poorly covered on exome. Knockdown of smoc2 in zebrafish showed pharyngeal teeth that had abnormalities reminiscent of the human phenotype. PMID: 23317772 Alfawaz et al., 2013 Consanguineous Pakistani family with oligodontia and microdontia. WES detected a homozygous SMOC2 c.681T>A (p.C227X) mutation in 2 affected individuals. PMID: 32908163 Morkmued et al., 2020 Same group as PMID: 22152679 Bloch-Zupan et al. Follow up of a 9yo female patient from the 2011 study. Radiographs showed severe oligodontia, microdontia, tooth root deficiencies, alveolar bone hypoplasia, and some skeletal dysplasia features: hyperlordotic curved spinal column, platyspondyly, wider iliac wings. Mouse model: homozygous smoc2 mutant mice had tooth number anomalies, reduced tooth size, altered enamel prism patterning, and spontaneous age-induced periodontal bone and root loss, supportive of disease association. SMOC2 is associated with AR Dentin dysplasia, type IA, OMIM:125400 in OMIM (accessed 5th Jun 2026). Sources: Literature |
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| Amelogenesis imperfecta v4.40 | SMOC2 | Ida Ertmanska Classified gene: SMOC2 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.40 | SMOC2 | Ida Ertmanska Gene: smoc2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.39 | SMOC2 | Ida Ertmanska changed review comment from: Comment on list classification: After review by the Genomics England Clinical Team, it was decided that Dentin Dysplasia is not in scope of the Amelogenesis imperfecta (AI) panel, as it is readily distinguishable from AI by dental specialists. Individuals reported with SMOC2 variants do not present with osteogenesis imperfecta. However, oligodontia and tooth shape abnormalities associated with this gene can be investigated through the R163 Ectodermal dysplasia panel. Hence, the rating should remain Red for Amelogenesis imperfecta, but SMOC2 will be proposed for promotion on the Ectodermal dysplasia panel.; to: Comment on list classification: After review by the Genomics England Clinical Team, it was decided that Dentin Dysplasia is not in scope of the Amelogenesis imperfecta (AI) panel, as it is readily distinguishable from AI by dental specialists. Individuals reported with SMOC2 variants do not present with osteogenesis imperfecta, either. However, oligodontia and tooth shape abnormalities associated with this gene can be investigated through the R163 Ectodermal dysplasia panel. Hence, the rating should remain Red for Amelogenesis imperfecta, but SMOC2 will be proposed for promotion on the Ectodermal dysplasia panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.39 | SMOC2 | Ida Ertmanska edited their review of gene: SMOC2: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.39 | SMOC2 | Ida Ertmanska commented on gene: SMOC2: Comment on list classification: After review by the Genomics England Clinical Team, it was decided that Dentin Dysplasia is not in scope of the Amelogenesis imperfecta (AI) panel, as it is readily distinguishable from AI by dental specialists. Individuals reported with SMOC2 variants do not present with osteogenesis imperfecta. However, oligodontia and tooth shape abnormalities associated with this gene can be investigated through the R163 Ectodermal dysplasia panel. Hence, the rating should remain Red for Amelogenesis imperfecta, but SMOC2 will be proposed for promotion on the Ectodermal dysplasia panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.39 | DSPP | Ida Ertmanska Classified gene: DSPP as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.39 | DSPP | Ida Ertmanska Gene: dspp has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.38 | DSPP | Ida Ertmanska edited their review of gene: DSPP: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.38 | DSPP | Ida Ertmanska commented on gene: DSPP: Comment on list classification: After review by the Genomics England Clinical Team, it was decided that Dentinogenesis Imperfecta (DI) is not in scope of the Amelogenesis imperfecta (AI) panel, as it is readily distinguishable from AI by dental specialists. Since individuals reported with DSPP variants do not present with osteogenesis imperfecta, there is currently no GMS panel this gene would fit into. The rating should remain Red for this indication. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.11 | ANAPC1 | Ida Ertmanska edited their review of gene: ANAPC1: Changed phenotypes to: Rothmund Thomson syndrome type 1, OMIM:618625, Rothmund-Thomson syndrome type 1, MONDO:0016368 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.11 | ANAPC1 | Ida Ertmanska Publications for gene: ANAPC1 were set to 31303264 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.10 | ANAPC1 | Ida Ertmanska Phenotypes for gene: ANAPC1 were changed from Rothmund Thomson syndrome type 1, OMIM:618625 to Rothmund Thomson syndrome type 1, OMIM:618625; Rothmund-Thomson syndrome type 1, MONDO:0016368 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | ANAPC1 | Ida Ertmanska reviewed gene: ANAPC1: Rating: ; Mode of pathogenicity: None; Publications: 38021400, 42210937; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | ANAPC1 | Ida Ertmanska Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | ANAPC1 | Ida Ertmanska Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | ANAPC1 | Ida Ertmanska edited their review of gene: ANAPC1: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | RECQL4 |
Ida Ertmanska changed review comment from: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teeth abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned.; to: PMID: 41628607 Genç et al., 2026 Report of 2 Turkish families: 3 sibs with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer), another male proband with a similar presentation and the same homozygous variant, and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All individuals had very low height, weight, and head circumference scores for their age. F1: All 3 affected sibs exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. The severity of microcephaly was -5.2 SD for the proband (III.2). Her younger brother, PIII.6, had head circumference of -3.9 SD, and older sister PIII.2 had head circumference of -2.2 SD at 12yrs old. Parents are first cousins. F2: Male proband presented with bilateral hearing loss, facial rash, and growth retardation. His head circumference was -4.1 SD below mean at 9 yrs old. Parents are first cousins. F3: 3yo male with chronic diarrhea and failure to thrive - present since 2 months of age. He developed facial and limb rashes at 9 months old. Alopecia, hyperkeratotic papules, and facial atrophy were also noted at 3 yrs old. Head circumference was noted to be -3.3 SD. Consanguineous parents. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teeth abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. |
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| Ectodermal dysplasia v5.9 | RECQL4 |
Ida Ertmanska changed review comment from: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. Ectodermal dysplasia findings: Poikiloderma (generalized) in 41/43 patients, Sparse hair/eyebrows and/or eyelashes noted in 29/43, and nail dysplasia was seen in 4/7 assessed probands. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teet abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. Sources: Literature; to: PMID: 41628607 Genç et al., 2026 Report of 2 Turkish families: 3 sibs with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer), another male proband with a similar presentation and the same homozygous variant, and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All individuals had very low height, weight, and head circumference scores for their age. F1: All 3 affected sibs exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. The severity of microcephaly was -5.2 SD for the proband (III.2). Her younger brother, PIII.6, had head circumference of -3.9 SD, and older sister PIII.2 had head circumference of -2.2 SD at 12yrs old. Parents are first cousins. F2: Male proband presented with bilateral hearing loss, facial rash, and growth retardation. His head circumference was -4.1 SD below mean at 9 yrs old. Parents are first cousins. F3: 3yo male with chronic diarrhea and failure to thrive - present since 2 months of age. He developed facial and limb rashes at 9 months old. Alopecia, hyperkeratotic papules, and facial atrophy were also noted at 3 yrs old. Head circumference was noted to be -3.3 SD. Consanguineous parents. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. Ectodermal dysplasia findings: Poikiloderma (generalized) in 41/43 patients, Sparse hair/eyebrows and/or eyelashes noted in 29/43, and nail dysplasia was seen in 4/7 assessed probands. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teet abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. Sources: Literature |
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| Severe microcephaly v9.34 | RECQL4 | Ida Ertmanska changed review comment from: Comment on list classification: Head circumference was not systematically measured or reported in historical RECQL4 cohorts; therefore, the frequency of microcephaly cannot be determined from those studies. In more recent reports (2025-2026), 3/4 probands assessed had microcephaly, with head circumference reported as lower than -3 SD in two cases and one of unknown severit. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: Head circumference was not systematically measured or reported in historical RECQL4 cohorts; therefore, the frequency of microcephaly cannot be determined from those studies. In three more recent reports (2025-2026), 5/6 probands assessed (2 likely related with the same homozygous Turkish founder variant) had microcephaly, with head circumference reported as lower than -3 SD. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.34 | RECQL4 |
Ida Ertmanska changed review comment from: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teeth abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. Sources: Literature; to: PMID: 41628607 Genç et al., 2026 Report of 2 Turkish families: 3 sibs with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer), another male proband with a similar presentation and the same homozygous variant, and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All individuals had very low height, weight, and head circumference scores for their age. F1: All 3 affected sibs exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. The severity of microcephaly was -5.2 SD for the proband (III.2). Her younger brother, PIII.6, had head circumference of -3.9 SD, and older sister PIII.2 had head circumference of -2.2 SD at 12yrs old. Parents are first cousins. F2: Male proband presented with bilateral hearing loss, facial rash, and growth retardation. His head circumference was -4.1 SD below mean at 9 yrs old. Parents are first cousins. F3: 3yo male with chronic diarrhea and failure to thrive - present since 2 months of age. He developed facial and limb rashes at 9 months old. Alopecia, hyperkeratotic papules, and facial atrophy were also noted at 3 yrs old. Head circumference was noted to be -3.3 SD. Consanguineous parents. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teeth abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. Sources: Literature |
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| Severe microcephaly v9.34 | RECQL4 | Ida Ertmanska changed review comment from: Comment on list classification: Head circumference was not systematically measured or reported in historical RECQL4 cohorts; therefore, the frequency of microcephaly cannot be determined from those studies. In more recent reports (2025-2026), 3/4 probands assessed had microcephaly, with head circumference reported as lower than -3 SD in two cases. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: Head circumference was not systematically measured or reported in historical RECQL4 cohorts; therefore, the frequency of microcephaly cannot be determined from those studies. In more recent reports (2025-2026), 3/4 probands assessed had microcephaly, with head circumference reported as lower than -3 SD in two cases and one of unknown severit. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.34 | RECQL4 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: RECQL4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.34 | RECQL4 | Ida Ertmanska commented on gene: RECQL4: Comment on list classification: Head circumference was not systematically measured or reported in historical RECQL4 cohorts; therefore, the frequency of microcephaly cannot be determined from those studies. In more recent reports (2025-2026), 3/4 probands assessed had microcephaly, with head circumference reported as lower than -3 SD in two cases. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.34 | RECQL4 | Ida Ertmanska Classified gene: RECQL4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.34 | RECQL4 | Ida Ertmanska Gene: recql4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | RECQL4 |
Ida Ertmanska changed review comment from: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teet abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned.; to: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teeth abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. |
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| Severe microcephaly v9.33 | RECQL4 |
Ida Ertmanska changed review comment from: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teet abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. Sources: Literature; to: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teeth abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. Sources: Literature |
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| Hereditary ataxia, adult onset v9.11 | OGDH |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects. Hence, this gene can be rated green in the next GMS update.; to: Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects. Note that the two different reported variants were shown to act via two different mechanisms (dominant negative vs gain of function). Hence, this gene can be rated amber with 'watchlist' tag added to review gene rating in light of any new evidence. |
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| Monogenic short stature v2.9 | RECQL4 | Ida Ertmanska reviewed gene: RECQL4: Rating: ; Mode of pathogenicity: None; Publications: 27247962, 38021400, 39324487, 40031098, 41628607; Phenotypes: Rothmund-Thomson syndrome, type 2, OMIM:268400, Rothmund-Thomson syndrome type 2, MONDO:0016369; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | RECQL4 | Ida Ertmanska Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.11 | OGDH | Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.11 | OGDH |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review was removed from gene: OGDH. Tag Q3_26_promote_green was removed from gene: OGDH. Tag watchlist tag was added to gene: OGDH. |
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| Intellectual disability v11.36 | KDM5B |
Ida Ertmanska changed review comment from: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Method: exome seq. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).; to: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Method: exome seq. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026). |
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| Intellectual disability v11.36 | KDM5B | Ida Ertmanska changed review comment from: Comment on mode of inheritance: After review by the Genomics England Clinical Team, the decision was made not to change the mode of inheritance of this gene. The gnomAD pLI score (probability of loss intolerance) is 0.00, suggesting this gene is not constrained for LoF variants. The underlying mechanism of the NDD is also yet to be elucidated. Hence, the MOI will remain 'BIALLELIC, autosomal or pseudoautosomal', until more evidence emerges for the MONOALLELIC association.; to: Comment on mode of inheritance: After review by the Genomics England Clinical Team, the decision was made not to change the mode of inheritance of this gene. The gnomAD pLI score (probability of loss intolerance) is 0.00, suggesting this gene is not constrained for LoF variants. The underlying mechanism of the dominant NDD is also yet to be elucidated. Hence, the MOI will remain 'BIALLELIC, autosomal or pseudoautosomal', until more evidence emerges for the MONOALLELIC association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | KDM5B |
Ida Ertmanska changed review comment from: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Method: exome seq. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).; to: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Method: exome seq. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026). |
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| Intellectual disability v11.36 | KDM5B | Ida Ertmanska edited their review of gene: KDM5B: Added comment: Comment on mode of inheritance: After review by the Genomics England Clinical Team, the decision was made not to change the mode of inheritance of this gene. The gnomAD pLI score (probability of loss intolerance) is 0.00, suggesting this gene is not constrained for LoF variants. The underlying mechanism of the NDD is also yet to be elucidated. Hence, the MOI will remain 'BIALLELIC, autosomal or pseudoautosomal', until more evidence emerges for the MONOALLELIC association.; Changed publications to: 37231097, 39202393, 40657596 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | KDM5B |
Ida Ertmanska changed review comment from: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Method: exome seq. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).; to: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Method: exome seq. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026). |
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| Respiratory ciliopathies including non-CF bronchiectasis v5.4 | WFDC2 |
Steven Cowman edited their review of gene: WFDC2: Added comment: Following on from the two studies (PMID 38626355 and 40401042) mentioned in previous reviews, there have now been two further reports. PMID 40114242 reported a total of six patients from five families with bronchiectasis of infantile or juvenile onset, all of whom also reported nasal polyps and sinusitis. Five were found to be homozygous for the c.291C > G; p.Cys97Trp variant, and one individual was compound heterozygous for c.291C > G; p.Cys97Trp and the novel c.278G > C; p.Cys93Ser variant. Both variants were predicted to be pathogenic. PMID 42717213 reported seven patients from five families, all of whom had severe bronchiectasis and chronic rhinosinusitis with onset in childhood and were homozygous for the c.291 C > G; p.Cys97Trp variant. The authors generated a Wfdc2 KO mouse model which exhibited severe respiratory failure at birth, which was not rescued by knock-in of a variant similar to the human p.Cys97Trp. Examination of lung tissue in both mouse lines found increased alveolar diameter, mucus accumulation in the trachea and neutrophil infiltration. EM found shorted tracheal cilia but normal axonemal structure. Further in vitro and in vivo work ultimately suggested that loss of WFDC2 function lead to ENaC hyperactivation (and resultant increased sodium reabsorption and mucus viscosity) leading to the observed phenotype.; Changed publications to: PMID: 38626355, 40401042, 40114242, 42717213 |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous, which would warrant an MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. However, their heterozygous parents were found to be unaffected carriers. Hence, an expert-review tag was added to this entry, to get wider NHSE opinion on the correct MOI, considering the technical limitations of WGS.; to: Comment on mode of inheritance: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous. This could warrant an MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, if there is a downstream clinical pathway to detect the somatic second hit. However, the heterozygous parents were found to be unaffected carriers. Hence, an expert-review tag was added to this entry, to get wider NHSE opinion on the correct MOI, considering the technical limitations of WGS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska changed review comment from: Comment on phenotypes: OMIM phenotype updated 25th Sept 2026.; to: Comment on phenotypes: OMIM phenotype updated 25th Sept 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous, which would warrant an MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. However, their heterozygous parents were found to be unaffected carriers. Hence, an expert-review tag was added to this entry, to get wider NHSE opinion on the correct MOI, considering the technical limitations of WGS.; to: Comment on mode of inheritance: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous, which would warrant an MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. However, their heterozygous parents were found to be unaffected carriers. Hence, an expert-review tag was added to this entry, to get wider NHSE opinion on the correct MOI, considering the technical limitations of WGS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska changed review comment from: Comment on phenotypes: OMIM phenotype updated 25th Sept 2026.; to: Comment on phenotypes: OMIM phenotype updated 25th Sept 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respiratory ciliopathies including non-CF bronchiectasis v5.4 | WFDC2 |
Steven Cowman changed review comment from: In addition to the 11 individuals reported in PMID 38626355 (see earlier review) there is now a further report (PMID 40401042) of three unrelated individuals from Japan with bronchiectasis who were all found to be homozygous for the same missense variant of WFDC2 (p.Cys97Trp). In keeping with the first series, all patients were reported to have upper lobe predominant bronchiectasis, sinus disease and low nasal NO, although ciliary ultrastructure was normal on EM and no pathogenic variants in CFTR or PCD-causing genes were found.; to: In addition to the 11 individuals reported in PMID 38626355 (see earlier review) there is now a further report (PMID 40401042) of three unrelated individuals from Japan with bronchiectasis who were all found to be homozygous for the same missense variant of WFDC2 (p.Cys97Trp). In keeping with the first series, all patients were reported to have upper lobe predominant bronchiectasis, sinus disease and low nasal NO, although ciliary ultrastructure was normal on EM and no pathogenic variants in CFTR or PCD-causing genes were found. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous. However, their heterozygous parents were found to be unaffected. Hence, the MOI should remain BIALLELIC, autosomal or pseudoautosomal, so that variants are not tiered in unaffected carriers.; to: Comment on list classification: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous, which would warrant an MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. However, their heterozygous parents were found to be unaffected carriers. Hence, an expert-review tag was added to this entry, to get wider NHSE opinion on the correct MOI, considering the technical limitations of WGS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska edited their review of gene: FADD: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: FADD. Tag Q3_26_MOI tag was added to gene: FADD. |
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| Paediatric disorders - additional genes v8.17 | NSMCE2 | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: NSMCE2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.17 | NSMCE2 | Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels (not on R27).; to: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.17 | NSMCE2 | Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels (not on R27).; to: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels (not on R27). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska Tag technical-limitations tag was added to gene: FADD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.87 | BRSK1 | Achchuthan Shanmugasundram edited their review of gene: BRSK1: Added comment: PMID:42805187 (2026) reported 10 individuals from seven families with heterozygous BRSK1 variants and neurodevelopmental disorder; only two unrelated individuals had epilepsy. Seizure was either absent or not reported in eight individuals from five unrelated families. The patients with seizures were identified with p.Arg237Cys or pGlu160Ter variant. The p.Arg237Cys variant was inherited from a mother with milder neurological/neuropsychiatric phenotype (ADHD, anxiety and depression), while the daughter had global developmental delay, autism, microcephaly, ADHD and seizures, suggesting incomplete penetrance for the variant.; Changed publications to: 42805187; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | BRSK1 |
Achchuthan Shanmugasundram changed review comment from: PMID:42805187 (2026) reported 10 individuals from seven families with heterozygous BRSK1 variants and neurodevelopmental disorder; only two individuals had epilepsy. Seizure was either absent or not reported in eight individuals from five unrelated families. These include three families with predicted loss-of-function variants, three independently arising de novo variants, and a de novo p.Gln428Ter allele segregating from an affected father to three affected children with variable developmental delay/intellectual disability. Two seizure-free missense variants showed partial loss of function in Drosophila rescue assays. Human reference BRSK1 rescued neuronal, behavioural and synaptic phenotypes caused by loss of the fly orthologue. Together with the independent Zhang et al. cohort (PMID:41035394, 2025) and heterozygous mouse model, the data support monoallelic BRSK1 loss of function as a cause of a variably expressive neurodevelopmental disorder. Developmental delay/intellectual disability can occur in the absence of epilepsy; therefore, the previous concern that cognitive impairment is secondary to early-onset seizures is no longer supported. This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype (last accessed 30 September 2026), but associated with green rating on the intellectual disability panel in PanelApp Australia.; to: PMID:42805187 (2026) reported 10 individuals from seven families with heterozygous BRSK1 variants and neurodevelopmental disorder; only two individuals had epilepsy. Seizure was either absent or not reported in eight individuals from five unrelated families. These include three families with predicted loss-of-function variants, three independently arising de novo variants, and a de novo p.Gln428Ter variant segregating from an affected father to three affected children with variable developmental delay/intellectual disability. The father and two sons with p.Gln428Ter variant displayed severe developmental delay/intellectual disability and microcephaly, whereas the daughter was only mildly affected suggesting incomplete penetrance for this variant. Two seizure-free missense variants showed partial loss of function in Drosophila rescue assays. Human reference BRSK1 rescued neuronal, behavioural and synaptic phenotypes caused by loss of the fly orthologue. Together with the independent Zhang et al. cohort (PMID:41035394, 2025) and heterozygous mouse model, the data support monoallelic BRSK1 loss of function as a cause of a variably expressive neurodevelopmental disorder. Developmental delay/intellectual disability can occur in the absence of epilepsy; therefore, the previous concern that cognitive impairment is secondary to early-onset seizures is no longer supported. This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype (last accessed 30 September 2026), but associated with green rating on the intellectual disability panel in PanelApp Australia. |
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| Paediatric or syndromic cardiomyopathy v8.14 | CRYAB |
Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: CRYAB. Tag Q3_26_promote_green tag was added to gene: CRYAB. |
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| Possible mitochondrial disorder, nuclear genes v5.25 | USMG5 | Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update.; to: Comment on list classification: There are 4 families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. Three of these families are of Ashkenazi Jewish ancestry, with probands harbouring the same homozygous founder variant. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.25 | USMG5 |
Ida Ertmanska changed review comment from: PMID: 40014158 İpek et al. 2025 4 Turkish brothers affected by mitochondrial disease, aged 13-25 yrs. All 4 had history of neurodegenerative disease, exhibited intellectual disability, muscle weakness, increased deep tendon reflexes in the lower extremities, spasticity, scoliosis, pes cavus deformity, positive Babinski reflex, abnormal gait patterns due to foot deformities, and normal cerebellar tests. Additional findings included geographic tongue (n = 2), strabismus (n = 2), nystagmus (n = 1), ophthalmoplegia (n = 2), hypertrophic upper extremity muscle body build (n = 2), keloid tissue (n = 1), and short stature (n = 3). ES identified a homozygous splice donor variant (c.87+1G > A) in the ATP5MK gene. Unaffected parents were het for the variant. The c.87+1G > A variant has 16 alleles reported in gnomAD, no homozygotes. PMID: 21345788 Ohsakaya et al., 2011 Knockdown of USMG5 (ATP5MK) in HeLa cells results in loss of ATP synthase in mitochondria. ATP5MK association with AR Leigh syndrome has been classified as Moderate in ClinGen (Mitochondrial Diseases GCEP, Aug 2020).; to: PMID: 40014158 İpek et al. 2025 4 Turkish brothers affected by mitochondrial disease, aged 13-25 yrs. All 4 had history of neurodegenerative disease, exhibited intellectual disability, muscle weakness, increased deep tendon reflexes in the lower extremities, spasticity, scoliosis, pes cavus deformity, positive Babinski reflex, abnormal gait patterns due to foot deformities, and normal cerebellar tests. Additional findings included geographic tongue (n = 2), strabismus (n = 2), nystagmus (n = 1), ophthalmoplegia (n = 2), hypertrophic upper extremity muscle body build (n = 2), keloid tissue (n = 1), and short stature (n = 3). ES identified a homozygous splice donor variant (c.87+1G > A) in the ATP5MK gene. Unaffected parents were het for the variant. The c.87+1G > A variant has 16 alleles reported in gnomAD, no homozygotes. PMID 29917077 Barca et al., 2018 Homozygous founder variant (NM_032747.3 c.87+1G>C) reported in three unrelated Ashkenazi Jewish families (allele freq 0.57% in Ashkenazi Jewish populations). Supportive functional studies are also reported: USMG5 mutated fibroblasts have reduced ATP synthesis. Transfection with wild-type USMG5 rescues CV dimerization and ATP production. PMID: 21345788 Ohsakaya et al., 2011 Knockdown of USMG5 (ATP5MK) in HeLa cells results in loss of ATP synthase in mitochondria. ATP5MK association with AR Leigh syndrome has been classified as Moderate in ClinGen (Mitochondrial Diseases GCEP, Aug 2020). |
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| Mitochondrial disorders v10.25 | USMG5 | Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update.; to: Comment on list classification: There are 4 families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. Three of these families are of Ashkenazi Jewish ancestry, with probands harbouring the same homozygous founder variant. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | USMG5 | Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update.; to: Comment on list classification: There are 4 families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. Three of these families are of Ashkenazi Jewish ancestry, with probands harbouring the same homozygous founder variant. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex V deficiency v3.7 | USMG5 | Ida Ertmanska changed review comment from: Comment on list classification: There are 2 unrelated families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update.; to: Comment on list classification: There are 4 families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. Three of these families are of Ashkenazi Jewish ancestry, with probands harbouring the same homozygous founder variant. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.43 | CD164 | Ida Ertmanska changed review comment from: Comment on list classification: There are now more than 3 unrelated families of various ancestries with the same heterozygous CD164 variant (p.Arg192Ter), which segregates in a dominant fashion with bilateral progressive hearing loss. Hence, this gene can be promoted to Green for Monogenic hearing loss.; to: Comment on list classification: There are now more than 3 unrelated families of various ancestries with the same heterozygous CD164 variant (p.Arg192Ter), which segregates in a dominant fashion with bilateral progressive hearing loss. There is also some supportive evidence from HEK cells and mouse expression studies. Hence, this gene can be promoted to Green for Monogenic hearing loss. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.43 | CD164 |
Ida Ertmanska changed review comment from: PMID: 35254497 Oziębło et al., 2022 Family 1 - large Polish pedigree with AD progressive hearing loss; CD164: c.574C>T, p.Arg192Ter segregated in affected individuals Family 2 - Korean family, 25 yo proband with bilateral progressive hearing loss onset around 22 years old; also het for CD164 p.Arg192Ter Same variant as reported in PMID 26197441 Nyegaard et al (2015) in a Danish family with hearing loss - recurrent hot spot mutation? CD164: c.574C>T, p.Arg192Ter - only 2 hets reported in gnomAD v4.1.1, MAF = 0.000001696 Age of onset of hearing loss for all 3 families ranged from newborn stage to adulthood. PMID: 36454368 Moresco et al., 2023 Family 7 - AD nonsyndromic hearing loss, affected individuals harboured het CD164: c.574C>T, p.Arg192Ter variant - segregated with disease. Seq method: Trio WES. The assocation between CD164 and autosomal dominant nonsyndromic hearing loss has been classified as Moderate by ClinGen Hearing Loss GCEP in 2024.; to: PMID: 35254497 Oziębło et al., 2022 Family 1 - large Polish pedigree with AD progressive hearing loss; CD164: c.574C>T, p.Arg192Ter segregated in affected individuals Family 2 - Korean family, 25 yo proband with bilateral progressive hearing loss onset around 22 years old; also het for CD164 p.Arg192Ter Same variant as reported in PMID 26197441 Nyegaard et al (2015) in a Danish family with hearing loss - recurrent hot spot mutation? CD164: c.574C>T, p.Arg192Ter - only 2 hets reported in gnomAD v4.1.1, MAF = 0.000001696 Age of onset of hearing loss for all 3 families ranged from newborn stage to adulthood. PMID: 36454368 Moresco et al., 2023 Family 7 - AD nonsyndromic hearing loss, affected individuals harboured het CD164: c.574C>T, p.Arg192Ter variant - segregated with disease. Seq method: Trio WES. Functional evidence: PMID: 26197441 - Nyegaard et al (2015): Functional studies in HEK cells demonstrated that the truncated p.Arg192Ter protein was almost completely retained on the plasma cell membrane in contrast to the WT protein, which targeted primarily to the endo-lysosomal compartments, implicating failed endocytosis as a possible disease mechanism. In addition, CD164 was found to be expressed in the mouse ear, in the inner and outer hair cells of the organ of Corti, as well as in other locations in the cochlear duct. The assocation between CD164 and autosomal dominant nonsyndromic hearing loss has been classified as Moderate by ClinGen Hearing Loss GCEP in 2024. |
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| Monogenic hearing loss v6.43 | CD164 | Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated families various ancestries with the same heterozygous CD164 variant (p.Arg192Ter), which segregates in a dominant fashion with bilateral progressive hearing loss. Hence, this gene can be promoted to Green for Monogenic hearing loss.; to: Comment on list classification: There are now more than 3 unrelated families of various ancestries with the same heterozygous CD164 variant (p.Arg192Ter), which segregates in a dominant fashion with bilateral progressive hearing loss. Hence, this gene can be promoted to Green for Monogenic hearing loss. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | HSPB1 | Eleanor Williams Tag Q3_26_NHS_review tag was added to gene: HSPB1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.17 | NSMCE2 | Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels.; to: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels (not on R27). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.17 | NSMCE2 | Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update.; to: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.17 | NSMCE2 | Ida Ertmanska Classified gene: NSMCE2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.17 | NSMCE2 | Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.17 | NSMCE2 | Ida Ertmanska Gene: nsmce2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.16 | NSMCE2 | Ida Ertmanska Publications for gene: NSMCE2 were set to 25105364; https://doi.org/10.1002/ajmg.a.70286 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.15 | NSMCE2 |
Ida Ertmanska changed review comment from: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before print Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans. His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD). PMID: 39184883 Tatiya, Kesri, and Ukey, 2024 14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made. PMID: 25105364 Payne et al., 2014 Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE. Additional evidence (Decipher case): Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026). Sources: Literature; to: PMID:42661287 Peduto et al., 2026 - online before print Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans. His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD). PMID: 39184883 Tatiya, Kesri, and Ukey, 2024 14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made. PMID: 25105364 Payne et al., 2014 Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE. Additional evidence (Decipher case): Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026). Sources: Literature |
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| Paediatric disorders - additional genes v8.15 | NSMCE2 | Ida Ertmanska edited their review of gene: NSMCE2: Changed publications to: 25105364, 42661287 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.15 | NSMCE2 |
Ida Ertmanska gene: NSMCE2 was added gene: NSMCE2 was added to Paediatric disorders - additional genes. Sources: Literature Q3_26_expert_review, Q3_26_promote_green tags were added to gene: NSMCE2. Mode of inheritance for gene: NSMCE2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NSMCE2 were set to 25105364; https://doi.org/10.1002/ajmg.a.70286 Phenotypes for gene: NSMCE2 were set to Seckel syndrome 10, OMIM:617253; Seckel syndrome, MONDO:0014991 Review for gene: NSMCE2 was set to GREEN Added comment: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before print Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans. His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD). PMID: 39184883 Tatiya, Kesri, and Ukey, 2024 14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made. PMID: 25105364 Payne et al., 2014 Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE. Additional evidence (Decipher case): Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026). Sources: Literature |
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| Skeletal dysplasia v10.13 | PAX3 | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: PAX3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.13 | PAX3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are now several patients reported with biallelic PAX3 variants and Waardenburg syndrome, type 3. These individuals often present with contractures, ulnar deviation, digit anomalies. Skeletal and limb anomalies are not reported in monoallelic cases. Hence, the mode of inheritance should be changed to "BIALLELIC, autosomal or pseudoautosomal" on Skeletal dysplasia at the next update. As this is a 'retraction' of the MONOALLELIC mode of inheritance, an expert-review tag was added, to ensure GMS agreement.; to: Comment on mode of inheritance: There are now several patients reported with biallelic PAX3 variants and Waardenburg syndrome, type 3. These individuals often present with contractures, ulnar deviation, digit anomalies. Skeletal and limb anomalies are not reported in monoallelic cases. Hence, the mode of inheritance should be changed to "BIALLELIC, autosomal or pseudoautosomal" on Skeletal dysplasia at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.22 | HSPB1 | Eleanor Williams Phenotypes for gene: HSPB1 were changed from Neuropathy, distal hereditary motor, type IIB, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595 to Neuronopathy, distal hereditary motor, autosomal dominant 3, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595; Charcot-Marie-Tooth disease axonal type 2F, MONDO:0011687) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.21 | HSPB1 | Eleanor Williams Publications for gene: HSPB1 were set to 15122254; 28379183 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.20 | HSPB1 |
Eleanor Williams Tag Q3_26_expert_review tag was added to gene: HSPB1. Tag Q3_26_promote_green tag was added to gene: HSPB1. |
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| Neurodegenerative disorders, adult onset v9.20 | HSPB1 | Eleanor Williams Classified gene: HSPB1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.20 | HSPB1 | Eleanor Williams Gene: hspb1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.43 | PAX3 | Eleanor Williams Phenotypes for gene: PAX3 were changed from #122880:Craniofacial-deafness-hand syndrome; #148820:Waardenburg syndrome, type 3; #193500:Waardenburg syndrome, type 1; #268220:Rhabdomyosarcoma 2, alveolar to orofacial cleft, MONDO:0000358; Waardenburg syndrome, type 1, OMIM:193500; Waardenburg syndrome type 1, MONDO:0008670; Craniofacial-deafness-hand syndrome,OMIM:122880; craniofacial-deafness-hand syndrome, MONDO:0007395 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.11 | PAX3 | Eleanor Williams Phenotypes for gene: PAX3 were changed from WAARDENBURG to orofacial cleft, MONDO:0000358; Waardenburg syndrome, type 1, OMIM:193500; Waardenburg syndrome type 1, MONDO:0008670 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.15 | PAX3 | Eleanor Williams Phenotypes for gene: PAX3 were changed from WAARDENBURG SYNDROME, TYPE 1; CRANIOFACIAL-DEAFNESS-HAND SYNDROME to Waardenburg syndrome, type 1, OMIM:193500; Waardenburg syndrome type 1, MONDO:0008670; Waardenburg syndrome, type 3, OMIM:148820; Waardenburg syndrome type 3, MONDO:0007862; Klein-Waardenburg syndromeCRANIOFACIAL-DEAFNESS-HAND SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.18 | PAX3 | Eleanor Williams Phenotypes for gene: PAX3 were changed from WAARDENBURG SYNDROME, TYPE 1; WS3; Waardenburg syndrome; WS1, WAARDENBURG SYNDROME, TYPE 3 to Waardenburg syndrome, type 1, OMIM:193500; Waardenburg syndrome type 1, MONDO:0008670; Waardenburg syndrome, type 3, OMIM:148820; Waardenburg syndrome type 3, MONDO:0007862; Klein-Waardenburg syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.13 | PAX3 | Eleanor Williams Phenotypes for gene: PAX3 were changed from Craniofacial-deafness-hand syndrome, 122880; Waardenburg syndrome, type 1, 193500; Waardenburg syndrome, type 3, 148820 to Waardenburg syndrome, type 1, OMIM:193500; Waardenburg syndrome type 1, MONDO:0008670; Waardenburg syndrome, type 3, OMIM:148820; Waardenburg syndrome type 3, MONDO:0007862; Klein-Waardenburg syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.14 | NSMCE2 | Eleanor Williams Added comment: Comment on publications: Peduto et al., 2026 paper is now in PubMed: 42661287 so added to list. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.14 | NSMCE2 | Eleanor Williams Publications for gene: NSMCE2 were set to 25105364; https://doi.org/10.1002/ajmg.a.70286 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.19 | SIGMAR1 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. The gene is therefore proposed for green rating. However, expert review from GLHs is sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility.; to: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. This gene is therefore proposed for green rating on this panel in the next GMS update. However, expert review from GLHs is sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.19 | SIGMAR1 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. Expert review from GLHs is therefore sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility.; to: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. The gene is therefore proposed for green rating. However, expert review from GLHs is sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.33 | NSMCE2 | Eleanor Williams Added comment: Comment on publications: Peduto et al., 2026 paper is now in PubMed: 42661287 so added to list. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.33 | NSMCE2 | Eleanor Williams Publications for gene: NSMCE2 were set to 25105364 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.19 | SIGMAR1 | Achchuthan Shanmugasundram Classified gene: SIGMAR1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.19 | SIGMAR1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Oliver Ziff and Luke Stuart, despite typical childhood onset, SIGMAR1-related disease can present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. Expert review from GLHs is therefore sought to determine whether SIGMAR1 should be included on this adult-onset panel in the context of diagnostic utility. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.19 | SIGMAR1 | Achchuthan Shanmugasundram Gene: sigmar1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.18 | SIGMAR1 | Achchuthan Shanmugasundram Publications for gene: SIGMAR1 were set to 21031579; 21842496; 25678561; 26078401; 26088963; 26088964; 27629094; 27821430; 30311446; 32600828; 326088964; 40309037; 41334667 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.17 | SIGMAR1 | Achchuthan Shanmugasundram Publications for gene: SIGMAR1 were set to 26088964; 26078401; 21031579; 26088963; 21842496; 27821430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.16 | SIGMAR1 | Achchuthan Shanmugasundram Phenotypes for gene: SIGMAR1 were changed from ?Amyotrophic lateral sclerosis 16, juvenile, OMIM:614373 to Autosomal recessive amyotrophic lateral sclerosis 16, juvenile, OMIM:614373; Neuronopathy, distal hereditary motor, autosomal recessive 2, OMIM:605726; amyotrophic lateral sclerosis type 16, MONDO:0013715 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | SIGMAR1 |
Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: SIGMAR1. Tag Q3_26_NHS_review tag was added to gene: SIGMAR1. Tag Q3_26_promote_green tag was added to gene: SIGMAR1. |
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| Early onset or syndromic epilepsy v9.87 | SLC12A5 | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: SLC12A5. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.12 | TBX6 | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.87 | SLC12A5 | Achchuthan Shanmugasundram Phenotypes for gene: SLC12A5 were changed from epilepsy of infancy with migrating focal seizures (EIMFS); Epileptic encephalopathy, early infantile, 34, 616645; {Epilepsy, idiopathic generalized, susceptibility to, 14}, 616685 to {Epilepsy, idiopathic generalized, susceptibility to, 14}, OMIM:616685; Developmental and epileptic encephalopathy 34, OMIM:616645 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.86 | SLC12A5 | Achchuthan Shanmugasundram Publications for gene: SLC12A5 were set to 26333769; 24668262; 27436767 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.30 | TBX6 | Achchuthan Shanmugasundram Classified gene: TBX6 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.30 | TBX6 | Achchuthan Shanmugasundram Gene: tbx6 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.29 | TBX6 | Achchuthan Shanmugasundram Phenotypes for gene: TBX6 were changed from Mullerian aplasia (MONDO:0019128); Mayer-Rokitansky-Kuster-Hauser syndrome (MONDO:0017771) to Mullerian aplasia, MONDO:0019128; Mayer-Rokitansky-Kuster-Hauser syndrome, MONDO:0017771 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.28 | TBX6 | Achchuthan Shanmugasundram Publications for gene: TBX6 were set to 36049007; 23954021 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.13 | TBX6 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Luke Stuart, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.13 | TBX6 | Achchuthan Shanmugasundram Mode of inheritance for gene: TBX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.12 | TBX6 | Achchuthan Shanmugasundram Phenotypes for gene: TBX6 were changed from Spondylocostal dysostosis 5 122600 to Spondylocostal dysostosis 5, OMIM:122600; spondylocostal dysostosis 5, MONDO:0007389 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.11 | TBX6 | Achchuthan Shanmugasundram Publications for gene: TBX6 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.10 | TBX6 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: TBX6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.12 | TBX6 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Luke Stuart, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.12 | TBX6 | Achchuthan Shanmugasundram Mode of inheritance for gene: TBX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.11 | TBX6 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Luke Stuart, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.11 | TBX6 | Achchuthan Shanmugasundram Mode of inheritance for gene: TBX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.10 | TBX6 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: TBX6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.10 | TBX6 | Achchuthan Shanmugasundram Phenotypes for gene: TBX6 were changed from Spondylocostal dysostosis 5 122600; Spondylocostal dysostosis 5 122600 to Spondylocostal dysostosis 5, OMIM:122600; spondylocostal dysostosis 5, MONDO:0007389 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.9 | TBX6 | Achchuthan Shanmugasundram Publications for gene: TBX6 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.37 | COL6A3 |
Luke Stuart changed review comment from: COL6A3 is associated with Bethlem myopathy 1C, OMIM #620726; Dystonia 27, OMIM #616411; Ullrich congenital muscular dystrophy 1C, OMIM #620728. As reviewed by Alexander Rossor, Villar-Quiles et al., 2026 (PMID 42520849) described Thirty-seven affected individuals from 32 families harbouring biallelic COL6A3 variants. All carried the recurrent c.7447A>G p.(Lys2483Glu) allele either in homozygosity (24 patients) or compound heterozygosity with a second (often truncating) COL6A3 variant (13 patients). Phase was confirmed in 28 cases. Genetic testing was performed via whole-exome sequencing (WES) or whole-genome sequencing (WGS) in 30 patients, and next-generation sequencing (NGS)-based myopathy panel in 7. The cohort demonstrated a consistent distal motor neuropathy-like/neuromyopathic phenotype with neurogenic electrophysiological findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). >70% of the patients showed motor conduction abnormalities, and needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%. All patients carried the recurrent c.7447A>G p.(Lys2483Glu) variant and, therefore, despite the presence of a minority of compound heterozygous patients, it remains unclear whether the observed neuropathy-like phenotype represents a variant-specific effect. In summary, this study provides strong evidence that distal motor neuropathy and neuromyopathy are part of the COL6A3 phenotypic spectrum. A green rating is therefore recommended for the Hereditary neuropathy or pain disorder panel.; to: COL6A3 is associated with Bethlem myopathy 1C, OMIM #620726; Dystonia 27, OMIM #616411; Ullrich congenital muscular dystrophy 1C, OMIM #620728. As reviewed by Alexander Rossor, Villar-Quiles et al., 2026 (PMID 42520849) described Thirty-seven affected individuals from 32 families harbouring biallelic COL6A3 variants. All carried the recurrent c.7447A>G p.(Lys2483Glu) allele either in homozygosity (24 patients) or compound heterozygosity with a second (often truncating) COL6A3 variant (13 patients). Phase was confirmed in 28 cases. Genetic testing was performed via whole-exome sequencing (WES) or whole-genome sequencing (WGS) in 30 patients, and next-generation sequencing (NGS)-based myopathy panel in 7. COL6A3 c.7447A>G p.(Lys2483Glu) is present in Gnomad v4 at a frequency of 1158/ 1614090 alleles including 1 homozygote. The cohort demonstrated a consistent distal motor neuropathy-like/neuromyopathic phenotype with neurogenic electrophysiological findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). >70% of the patients showed motor conduction abnormalities, and needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%. All patients carried the recurrent c.7447A>G p.(Lys2483Glu) variant and, therefore, despite the presence of a minority of compound heterozygous patients, it remains unclear whether the observed neuropathy-like phenotype represents a variant-specific effect. In summary, this study provides strong evidence that distal motor neuropathy and neuromyopathy are part of the COL6A3 phenotypic spectrum. A green rating is therefore recommended for the Hereditary neuropathy or pain disorder panel. |
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| Proteinuric renal disease v6.22 | PTPRO | Achchuthan Shanmugasundram Publications for gene: PTPRO were set to 21722858; 30065916; 34546508; 21722858 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.21 | PTPRO | Achchuthan Shanmugasundram Publications for gene: PTPRO were set to 21722858; 30065916 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.20 | PTPRO | Achchuthan Shanmugasundram Mode of inheritance for gene: PTPRO was changed from to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | SIGMAR1 |
Luke Stuart changed review comment from: SIGMAR1 is provisionally associated with autosomal recessive Amyotrophic lateral sclerosis 16, juvenile (OMIM:614373) and Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726) (accessed 10/2026). Multiple patients with biallelic variants have been identified, and disease onset is typically in the first decade (Kalita et al. (2025), PMID 41334667; Al-Saif et al. (2011), PMID 21842496, Horga et al. (2016) PMID 27629094). Disruption of Sigmar1 in the mouse leads to locomotor deficit (Bernard-Marissal et al. (2015), PMID 25678561). Biallelic SIGMAR1 variants typically cause a phenotypic spectrum encompassing juvenile ALS16 and distal hereditary motor neuropathy with pyramidal signs. Recent evidence supports a spectrum of SIGMAR1-related motor neuropathy, with the slowly progressive, distal-predominant phenotype generally favouring dHMN over classical ALS (Yu et al. (2025), PMID 40309037; Kalita et al. (2025), PMID 41334667)). Adult presentation is documented in isolated cases. Ma et al. (2020), PMID 32600828 reported onset at 34 years in a patient with compound-heterozygous c.247T>C and c.545T>C variants who was referred to an ALS clinic with distal weakness and hyperreflexia; the authors classified the phenotype as dHMN mimicking ALS. An additional Japanese patient developed ALS at 80 years with compound-heterozygous missense variants, though notably, one of the variants (p.R208W) has an allele frequency of 2.9% in East Asians via gnomad v4 and 64 homozygotes across all populations (Izumi et al. (2018), PMID 30311446). Evidence implicating SIGMAR1 in typical adult-onset ALS or ALS–FTD remains disputed (Pickering-Brown et al. (2015), PMID 26088964). SIGMAR1 c.672*51G>T was identified in 3 families with ALS-FTD, though later studies found one of the families also to harbored a C9ORF72 expansion (Luty et al. (2010), PMID 21031579. As reviewed by Oliver Ziff, despite typical childhood onset, SIGMAR1-related disease can thus present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. Expert review is therefore warranted to determine whether SIGMAR1 should be included on the adult-onset neurodegenerative disorders panel in the context of diagnostic utility, rather than on relation to a definitive association between SIGMAR1 and adult-onset neurodegeneration.; to: SIGMAR1 is provisionally associated with autosomal recessive Amyotrophic lateral sclerosis 16, juvenile (OMIM:614373) and Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726) (accessed 10/2026). Multiple patients with biallelic variants have been identified, and disease onset is typically in the first decade (Kalita et al. (2025), PMID 41334667; Al-Saif et al. (2011), PMID 21842496, Horga et al. (2016) PMID 27629094). Disruption of Sigmar1 in the mouse leads to locomotor deficit (Bernard-Marissal et al. (2015), PMID 25678561). Biallelic SIGMAR1 variants typically cause a phenotypic spectrum encompassing juvenile ALS16 and distal hereditary motor neuropathy with pyramidal signs. Recent evidence supports a spectrum of SIGMAR1-related motor neuropathy, with the slowly progressive, distal-predominant phenotype generally favouring dHMN over classical ALS (Yu et al. (2025), PMID 40309037; Kalita et al. (2025), PMID 41334667)). Adult presentation is documented in isolated cases. Ma et al. (2020), PMID 32600828 reported onset at 34 years in a patient with compound-heterozygous c.247T>C and c.545T>C variants who was referred to an ALS clinic with distal weakness and hyperreflexia; the authors classified the phenotype as dHMN mimicking ALS. An additional Japanese patient developed ALS at 80 years with compound-heterozygous missense variants, though notably, one of the variants (p.R208W) has an allele frequency of 2.9% in East Asians via gnomad v4 and 64 homozygotes across all populations (Izumi et al. (2018), PMID 30311446). Evidence implicating SIGMAR1 in typical adult-onset ALS or ALS–FTD remains disputed (Pickering-Brown et al. (2015), PMID 26088964). SIGMAR1 c.672*51G>T was identified in 3 families with ALS-FTD, though later studies found one of the families also to harbored a C9ORF72 expansion (Luty et al. (2010), PMID 21031579. As reviewed by Oliver Ziff, despite typical childhood onset, SIGMAR1-related disease can thus present in adulthood or enter an adult ALS/LMN pathway because of overlapping clinical presentation. Expert review is therefore warranted to determine whether SIGMAR1 should be included on the adult-onset neurodegenerative disorders panel in the context of diagnostic utility, rather than in relation to a definitive association between SIGMAR1 and adult-onset neurodegeneration. |
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| Neurodegenerative disorders, adult onset v9.15 | SIGMAR1 | Luke Stuart reviewed gene: SIGMAR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 41334667, 21842496, 27629094, 25678561, 40309037, 32600828, 30311446, 26088964, 21031579; Phenotypes: Autosomal recessive amyotrophic lateral sclerosis 16, juvenile (OMIM:614373), Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726), amyotrophic lateral sclerosis type 16 (MONDO:0013715); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | COL4A5 | Aakash Joshi reviewed gene: COL4A5: Rating: AMBER; Mode of pathogenicity: None; Publications: PMCID 11121527, PMCID 11053243, PMCID 10910213; Phenotypes: cystic renal disease; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.36 | CLCN3 | Achchuthan Shanmugasundram Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517 to ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517; Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.10 | CLCN3 | Achchuthan Shanmugasundram Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517 to ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517; Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.9 | CLCN3 | Achchuthan Shanmugasundram Publications for gene: CLCN3 were set to 34186028; 36536096 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.85 | CLCN3 | Achchuthan Shanmugasundram Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517 to ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517; Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.8 | CLCN3 | Achchuthan Shanmugasundram Publications for gene: CLCN3 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | MUC1 | Aakash Joshi reviewed gene: MUC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMCID 11068942, PMID 24509297; Phenotypes: cystic renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | SEC61A1 | Aakash Joshi reviewed gene: SEC61A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMCID 11045796, PMID 36478640; Phenotypes: cystic renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | REN |
Aakash Joshi gene: REN was added gene: REN was added to Cystic kidney disease. Sources: Literature Mode of inheritance for gene: REN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: REN were set to PMCID 11997664 Phenotypes for gene: REN were set to cystic renal disease Penetrance for gene: REN were set to unknown Review for gene: REN was set to RED Added comment: PMCID 11997664 identified in a cohort of 702 individuals with suspected inherited renal cystic disease that 1 individual had a monoallelic pathogenic REN variant. Would suggest this provides some evidence for inclusion but would be low (Red list). Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.15 | HSPB1 | Luke Stuart edited their review of gene: HSPB1: Changed mode of pathogenicity: Other; Changed phenotypes to: Neuropathy, distal hereditary motor, type IIB, OMIM:608634, Charcot-Marie-Tooth disease, type 2F, OMIM:606595, Charcot-Marie-Tooth disease axonal type 2F (MONDO:0011687) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | HSPB1 | Luke Stuart edited their review of gene: HSPB1: Changed publications to: 27492805, 17623484, 28797631, 15122254, 27816334 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | HSPB1 |
Luke Stuart changed review comment from: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254). Evidence for a direct association with classical ALS is limited: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as a potential risk modifier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection. Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association.; to: Variants in HSPB1 are a recurrent and established cause of distal Hereditary Motor Neuropathy (dHMN), and are associated with Charcot-Marie-Tooth disease, axonal, type 2F (CMT2F, OMIM:606595) and Neuronopathy, distal hereditary motor, autosomal dominant 3 (OMIM:608634) (accessed 10/2026). In a cohort of 301 individuals with CMT and 115 with distal hereditary motor neuropathy, a segregating HSPB1 missense variant was identified in a Russian CMT2F family, with four additional missense variants found across four distal-HMN families; mutant HSPB1 reduced neuronal-cell viability and disrupted neurofilament assembly (Evgrafov et al., (2004), PMID 15122254). As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease- in a natural history study of HSBP1 neuropathy, patients developed adult-onset progressive weakness, wasting and chronic denervation (Rossor et al. (2016), PMID 27816334. Evidence for a direct association with classical ALS is limited and equivocal: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as a potential risk modifier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection. Expert review is recommended to determine whether HSPB1 should be included in the adult onset neurodegenerative disorders panel to capture patients with HSPB1-related neuropathy who clinically mimic progressive muscular atrophy or motor neuron disease, rather than as an established cause of motor neuron disease. |
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| Early onset or syndromic epilepsy v9.84 | SLC12A5 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. An expert_review rating was added to ensure GMS agreement on this change.; to: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.84 | ATP6V1A |
Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are more than 30 individuals reported in literature with heterozygous de novo missense variants in ATP6V1A and a Developmental and epileptic encephalopathy (including early onset seizures in at least 28 cases). There are also 6 probands reported with biallelic ATP6V1A variants, of which only 2 presented with seizures. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. As this is a demotion of the BIALLELIC MOI, an expert_review tag was also added.; to: Comment on mode of inheritance: There are more than 30 individuals reported in literature with heterozygous de novo missense variants in ATP6V1A and a Developmental and epileptic encephalopathy (including early onset seizures in at least 28 cases). There are also 6 probands reported with biallelic ATP6V1A variants, of which only 2 presented with seizures. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. |
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| Early onset or syndromic epilepsy v9.84 | ATP6V1A |
Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: ATP6V1A. Tag Q3_26_expert_review was removed from gene: ATP6V1A. Tag Q3_26_MOI tag was added to gene: ATP6V1A. |
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| Intellectual disability v11.35 | CLCN3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.84 | CLCN3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | CLCN3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.35 | CLCN3 | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: CLCN3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.84 | CLCN3 | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: CLCN3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | CLCN3 | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: CLCN3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | LBR | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: LBR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | LBR | Ida Ertmanska changed review comment from: Comment on mode of inheritance: Pelger-Huet anomaly, seen in numerous carriers of heterozygous LBR variants, does not usually cause any symptoms and thus it is considered a benign condition. There is also one patient reported with a het LBR variant and Reynolds syndrome. However, the variant is present in homozygous state in gnomAD, and its significance is hard to determine. Hence, the mode of inheritance should be changed to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. An expert_review tag has been added to ensure GMS agreement with this demotion.; to: Comment on mode of inheritance: Pelger-Huet anomaly, seen in numerous carriers of heterozygous LBR variants, does not usually cause any symptoms and thus it is considered a benign condition. There is also one patient reported with a het LBR variant and Reynolds syndrome. However, the variant is present in homozygous state in gnomAD, and its significance is hard to determine. Hence, the mode of inheritance should be changed to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | HSPB1 | Luke Stuart edited their review of gene: HSPB1: Changed publications to: 27492805, 17623484, 28797631, 15122254 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.35 | BRSK1 | Achchuthan Shanmugasundram Classified gene: BRSK1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.35 | BRSK1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: Intellectual disability without seizures was reported in at least three unrelated families with monoallelic BRSK1 variants. Hence, this gene can be promoted to green rating on this panel in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.35 | BRSK1 | Achchuthan Shanmugasundram Gene: brsk1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.34 | BRSK1 |
Achchuthan Shanmugasundram changed review comment from: PMID:42805187 (2026) reported 10 individuals from seven families with heterozygous BRSK1 variants and neurodevelopmental disorder; only two individuals had epilepsy. Either seizure was absent or not reported in eight individuals from five unrelated families. These include three families with predicted loss-of-function variants, three independently arising de novo variants, and a de novo p.Gln428Ter allele segregating from an affected father to three affected children with variable developmental delay/intellectual disability. Two seizure-free missense variants showed partial loss of function in Drosophila rescue assays. Human reference BRSK1 rescued neuronal, behavioural and synaptic phenotypes caused by loss of the fly orthologue. Together with the independent Zhang et al. cohort (PMID:41035394, 2025) and heterozygous mouse model, the data support monoallelic BRSK1 loss of function as a cause of a variably expressive neurodevelopmental disorder. Developmental delay/intellectual disability can occur in the absence of epilepsy; therefore, the previous concern that cognitive impairment is secondary to early-onset seizures is no longer supported. This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype (last accessed 30 September 2026), but associated with green rating on the intellectual disability panel in PanelApp Australia.; to: PMID:42805187 (2026) reported 10 individuals from seven families with heterozygous BRSK1 variants and neurodevelopmental disorder; only two individuals had epilepsy. Seizure was either absent or not reported in eight individuals from five unrelated families. These include three families with predicted loss-of-function variants, three independently arising de novo variants, and a de novo p.Gln428Ter allele segregating from an affected father to three affected children with variable developmental delay/intellectual disability. Two seizure-free missense variants showed partial loss of function in Drosophila rescue assays. Human reference BRSK1 rescued neuronal, behavioural and synaptic phenotypes caused by loss of the fly orthologue. Together with the independent Zhang et al. cohort (PMID:41035394, 2025) and heterozygous mouse model, the data support monoallelic BRSK1 loss of function as a cause of a variably expressive neurodevelopmental disorder. Developmental delay/intellectual disability can occur in the absence of epilepsy; therefore, the previous concern that cognitive impairment is secondary to early-onset seizures is no longer supported. This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype (last accessed 30 September 2026), but associated with green rating on the intellectual disability panel in PanelApp Australia. |
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| Intellectual disability v11.34 | BRSK1 |
Achchuthan Shanmugasundram changed review comment from: PMID:42805187 (2026) reported 10 individuals from seven families with heterozygous BRSK1 variants and neurodevelopmental disorder; only two individuals had epilepsy. Either seizure was absent or not reported in eight individuals from five unrelated families. These include three families with predicted loss-of-function variants, three independently arising de novo variants, and a de novo p.Gln428Ter allele segregating from an affected father to three affected children with variable developmental delay/intellectual disability. Two seizure-free missense variants showed partial loss of function in Drosophila rescue assays. Human reference BRSK1 rescued neuronal, behavioural and synaptic phenotypes caused by loss of the fly orthologue. Together with the independent Zhang et al. cohort (PMID:41035394, 2025) and heterozygous mouse model, the data support monoallelic BRSK1 loss of function as a cause of a variably expressive neurodevelopmental disorder. Developmental delay/intellectual disability can occur in the absence of epilepsy; therefore, the previous concern that cognitive impairment is secondary to early-onset seizures is no longer supported. This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype (last accessed), but associated with green rating on the intellectual disability panel in PanelApp Australia.; to: PMID:42805187 (2026) reported 10 individuals from seven families with heterozygous BRSK1 variants and neurodevelopmental disorder; only two individuals had epilepsy. Either seizure was absent or not reported in eight individuals from five unrelated families. These include three families with predicted loss-of-function variants, three independently arising de novo variants, and a de novo p.Gln428Ter allele segregating from an affected father to three affected children with variable developmental delay/intellectual disability. Two seizure-free missense variants showed partial loss of function in Drosophila rescue assays. Human reference BRSK1 rescued neuronal, behavioural and synaptic phenotypes caused by loss of the fly orthologue. Together with the independent Zhang et al. cohort (PMID:41035394, 2025) and heterozygous mouse model, the data support monoallelic BRSK1 loss of function as a cause of a variably expressive neurodevelopmental disorder. Developmental delay/intellectual disability can occur in the absence of epilepsy; therefore, the previous concern that cognitive impairment is secondary to early-onset seizures is no longer supported. This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype (last accessed 30 September 2026), but associated with green rating on the intellectual disability panel in PanelApp Australia. |
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| Intellectual disability v11.34 | BRSK1 | Achchuthan Shanmugasundram Mode of inheritance for gene: BRSK1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.33 | BRSK1 | Achchuthan Shanmugasundram Publications for gene: BRSK1 were set to 41035394 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.32 | BRSK1 | Achchuthan Shanmugasundram Phenotypes for gene: BRSK1 were changed from Neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.31 | BRSK1 | Achchuthan Shanmugasundram Tag Q3_26_NHS_review was removed from gene: BRSK1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.31 | BRSK1 |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: BRSK1. Tag Q3_26_promote_green tag was added to gene: BRSK1. |
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| Intellectual disability v11.31 | BRSK1 | Achchuthan Shanmugasundram reviewed gene: BRSK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 42805187; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.25 | SLC22A5 | Matthew Edwards reviewed gene: SLC22A5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31373028, PMID: 42480505; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | HSPB1 |
Luke Stuart changed review comment from: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254. Evidence for classical ALS remains limited: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as apotential risk mofidiier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection. The association with a broad adult-onset neurodegenerative phenotype is uncertain. Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association.; to: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254). Evidence for a direct association with classical ALS is limited: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as a potential risk modifier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection. Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association. |
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| Neurodegenerative disorders, adult onset v9.15 | HSPB1 |
Luke Stuart changed review comment from: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254. Evidence for classical ALS remains limited: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as apotential risk mofidiier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection. The association with a broad adult-onset neurodegenerative phenotype is uncertain. Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association.; to: As reviewed by Oliver Ziff, adult-onset HSPB1-related motor neuropathy may clinically resemble progressive muscular atrophy or motor neuron disease (Evgrafov et al., (2004), PMID 15122254. Evidence for classical ALS remains limited: Capponi et al. (2016), PMID 27492805, identified two variants in 247 patients with ALS, (c.570G>C, p.Gln190His and c.610dupG, p.Ala204GlyfsTer6); the latter impaired HSPB1 chaperone activity in vitro; Dierick et al. (2007), PMID 17623484, identified a functional promoter variant HSPB1 c.-217T>C in one patient reducing transcriptional activity by 50% and proposed as apotential risk mofidiier in motor neuron disease pathogenesis. Heilman et al. (2017), PMID 28797631, showed that neuropathy-associated HSPB1 variants p.Gly84Arg and p.Arg136Trp attenuated astrocytic HSPB1-mediated motor neuron protection. The association with a broad adult-onset neurodegenerative phenotype is uncertain. Expert review is recommended to determine whether inclusion in the adult onset neurodegenerative disorder panel is warranted as coverage for a motor neuron disease mimic rather than an established classical ALS association. |
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| Neurodegenerative disorders, adult onset v9.15 | HSPB1 | Luke Stuart reviewed gene: HSPB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27492805, 17623484, 28797631; Phenotypes: Neuropathy, distal hereditary motor, type IIB, OMIM:608634, Charcot-Marie-Tooth disease, type 2F, OMIM:606595; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | UROD | Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Luke Stuart, biallelic pathogenic variants in UROD cause hepatoerythropoietic porphyria - an inborn error of haem biosynthesis. While monoallelic variants are known to cause familial porphyria cutanea tarda, the penetrance is low and extra-cutaneous features are unlikely to be present. Hence, the mode of inheritance should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BIALLELIC, autosomal or pseudoautosomal' at the next update.; to: Comment on mode of inheritance: As reviewed by Luke Stuart, biallelic pathogenic variants in UROD cause hepatoerythropoietic porphyria - an inborn error of haem biosynthesis. While monoallelic variants are known to cause familial porphyria cutanea tarda, the penetrance is low and extra-cutaneous features are unlikely to be present. Hence, the mode of inheritance should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BIALLELIC, autosomal or pseudoautosomal' at the next update. An expert review tag was added to ensure GMS agreement on this proposed MOI demotion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.35 | UROD | Ida Ertmanska Publications for gene: UROD were set to 27604308 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.34 | UROD |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: UROD. Tag Q3_26_MOI tag was added to gene: UROD. |
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| Likely inborn error of metabolism v9.34 | UROD | Ida Ertmanska reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria, hepatoerythropoietic, OMIM:176100, Porphyria cutanea tarda, OMIM:176100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.34 | UROD |
Luke Stuart changed review comment from: Biallelic pathogenic variants in UROD cause hepatoerythropoietic porphyria (OMIM: 176100), an autosomal recessive inborn error of haem biosynthesis characterised by markedly reduced uroporphyrinogen decarboxylase activity (Sassa et al., 1987, PMID 3821794; PMID: Romana et al., 1991, PMID 1905636; To-Figueras et al., 2011, PMID: 21668429). In addition to its characteristic childhood-onset cutaneous phenotype, affected individuals may present with red or dark urine, markedly abnormal urinary, plasma, faecal and erythrocyte porphyrins, and chronic anaemia or haemolysis (Cantatore-Francis et al., 2010, PMID: 20479301; To-Figueras et al., 2011, PMID: 21668429). Although non-cutaneous phenotypes are unusual, as noted by Elder et al., 1997, PMID 9211196, amongst 18 cases of HEP with confirmed biallelic variants and accessible clinical details, four had hepatomegaly (Cruces Prado et al., 1980, PMID 7398998) or splenomegaly (Sassa et al., 1987, PMID 3821794) or both (To-Figueras et al., 2011, PMID 21668429; Roberts et al., 1995, PMID: 7706766). Biallelic UROD-related HEP is therefore potentially relevant to the likely inborn error of metabolism panel, particularly for individuals with unexplained porphyrin abnormalities, red or dark urine, anaemia or haemolysis, or a multisystem presentation accompanied by cutaneous photosensitivity or skin fragility. Due to the low penetrance of monoallelic UROD variants (causing porphyria cutanea tarda, PCT) and lower likelihood of presenting extra-dermatological features, inheritance is recommended as biallelic only for likely inborn error of metabolism panel.; to: Biallelic pathogenic variants in UROD cause hepatoerythropoietic porphyria (OMIM: 176100), an autosomal recessive inborn error of haem biosynthesis characterised by markedly reduced uroporphyrinogen decarboxylase activity (Sassa et al., 1987, PMID 3821794; PMID Romana et al., 1991, PMID 1905636; To-Figueras et al., 2011, PMID 21668429). In addition to its characteristic childhood-onset cutaneous phenotype, affected individuals may present with red or dark urine, markedly abnormal urinary, plasma, faecal and erythrocyte porphyrins, and chronic anaemia or haemolysis (Cantatore-Francis et al., 2010, PMID: 20479301; To-Figueras et al., 2011, PMID 21668429). Although non-cutaneous phenotypes are unusual, as noted by Elder et al., 1997, PMID 9211196, amongst 18 cases of HEP with confirmed biallelic variants and accessible clinical details, four had hepatomegaly (Cruces Prado et al., 1980, PMID 7398998) or splenomegaly (Sassa et al., 1987, PMID 3821794) or both (To-Figueras et al., 2011, PMID 21668429; Roberts et al., 1995, PMID: 7706766). Biallelic UROD-related HEP is therefore potentially relevant to the likely inborn error of metabolism panel, particularly for individuals with unexplained porphyrin abnormalities, red or dark urine, anaemia or haemolysis, or a multisystem presentation accompanied by cutaneous photosensitivity or skin fragility. Due to the low clinical penetrance of monoallelic UROD variants causing familial porphyria cutanea tarda (PCT), the requirement for additional precipitating factors for overt disease, and the lower severity and likelihood of extra-dermatological features, biallelic inheritance only is recommended for the likely inborn error of metabolism panel. |
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| Leukodystrophy, adult onset v7.12 | PSAP | Ida Ertmanska edited their review of gene: PSAP: Changed phenotypes to: Metachromatic leukodystrophy due to SAP-b deficiency, OMIM:249900, metachromatic leukodystrophy due to saposin B deficiency, MONDO:0009590 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.12 | PSAP | Ida Ertmanska edited their review of gene: PSAP: Changed publications to: 31289144, 37404680 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.12 | PSAP |
Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: PSAP. Tag Q3_26_demote_red tag was added to gene: PSAP. |
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| Leukodystrophy, adult onset v7.12 | PSAP | Ida Ertmanska changed review comment from: Comment on list classification: While there are numerous individuals reported in literature with biallelic PSAP variants and Metachromatic leukodystrophy, there is only one patient with symptom onset after 18 years of age. Thus, this gene is not in scope of the 'Leukodystrophy, adult onset' and should be demoted to Red rating.; to: Comment on list classification: While there are numerous individuals reported in literature with biallelic PSAP variants and Metachromatic leukodystrophy, there is only one patient with symptom onset after 18 years of age. Most individuals present in infancy or during the early years of childhood. Thus, this gene is not in scope of the 'Leukodystrophy, adult onset', and should be demoted to Red rating, until more evidence emerges. An expert-review tag was added to ensure GMS agreement on this demotion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.12 | PSAP |
Ida Ertmanska Tag Q3_26_demote_red was removed from gene: PSAP. Tag Q3_26_demote_amber tag was added to gene: PSAP. |
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| Leukodystrophy, adult onset v7.12 | PSAP |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: PSAP. Tag Q3_26_demote_red tag was added to gene: PSAP. |
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| Leukodystrophy, adult onset v7.12 | PSAP | Ida Ertmanska commented on gene: PSAP: Comment on list classification: While there are numerous individuals reported in literature with biallelic PSAP variants and Metachromatic leukodystrophy, there is only one patient with symptom onset after 18 years of age. Thus, this gene is not in scope of the 'Leukodystrophy, adult onset' and should be demoted to Red rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.12 | PSAP |
Ida Ertmanska changed review comment from: PMID: 31289144 Fenu et al., 2019 Case report of a 29yo female patient with Metachromatic leukodystrophy and comp het PSAP variants: c.645C>A and c.665T>C. Age of disease onset was after age 22yrs. She presented with behavioural and cognitive decline. She was also treated for postpartum depression since early 20s. No motor disturbance except a mild tremor in her hands. Brain MRI showed diffuse leukoencephalopathy, and ENMG revealed a severe demyelinating polyneuropathy. Sural nerve biopsy showed characteristic MLD inclusions. Study specifically says that 'this is the first adult-onset case' reported for this association. ClinGen classified the association between PSAP and AR "metachromatic leukodystrophy due to saposin B deficiency" as Definitive (Lysosomal Diseases GCEP, 07/20/2023). All of the 9 probands included in this curation we under the age of 8 years at time of report.; to: PMID: 31289144 Fenu et al., 2019 Case report of a 29yo female patient with Metachromatic leukodystrophy and comp het PSAP variants: c.645C>A, p.Asn215Lys and c.665T>C, p.Leu222Ser. Variant p.Leu222Ser suggested to have a milder effect on protein function. Age of disease onset was after age 22yrs. She presented with behavioural and cognitive decline. She was also treated for postpartum depression since early 20s. No motor disturbance except a mild tremor in her hands. Brain MRI showed diffuse leukoencephalopathy, and ENMG revealed a severe demyelinating polyneuropathy. Sural nerve biopsy showed characteristic MLD inclusions. High levels of urinary sulfatides noted. Study specifically says that 'this is the first adult-onset case' reported for this association. PMID: 37404680 Sheth et al., 2023 Case 2 - 19yo male Indian patient who presented with gait ataxia, difficulty in walking and nystagmus - labelled 'adult‐onset', however his symptoms had started at age 13 years. His MRI brain revealed confluent and symmetrical areas of T2W/FLAIR hyperintensities in the periventricular and deep white matter of bilateral cerebral hemispheres, centrum semiovale and corpus callosum. Mild thinning of the corpus callosum was also seen. He was homozygous for PSAP c.593G > A, p.Cys198Tyr. Method: targeted seq panel of 23 genes. ClinGen classified the association between PSAP and AR "metachromatic leukodystrophy due to saposin B deficiency" as Definitive (Lysosomal Diseases GCEP, 07/20/2023). All of the 9 probands included in this curation were under the age of 8 years at time of report. |
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| Leukodystrophy, adult onset v7.12 | PSAP |
Ida Ertmanska changed review comment from: PMID: 31289144 Fenu et al., 2019 ClinGen classified the association between PSAP and AR "metachromatic leukodystrophy due to saposin B deficiency" as Definitive (Lysosomal Diseases GCEP, 07/20/2023). All of the 9 probands included in this curation we under the age of 8 years at time of report.; to: PMID: 31289144 Fenu et al., 2019 Case report of a 29yo female patient with Metachromatic leukodystrophy and comp het PSAP variants: c.645C>A and c.665T>C. Age of disease onset was after age 22yrs. She presented with behavioural and cognitive decline. She was also treated for postpartum depression since early 20s. No motor disturbance except a mild tremor in her hands. Brain MRI showed diffuse leukoencephalopathy, and ENMG revealed a severe demyelinating polyneuropathy. Sural nerve biopsy showed characteristic MLD inclusions. Study specifically says that 'this is the first adult-onset case' reported for this association. ClinGen classified the association between PSAP and AR "metachromatic leukodystrophy due to saposin B deficiency" as Definitive (Lysosomal Diseases GCEP, 07/20/2023). All of the 9 probands included in this curation we under the age of 8 years at time of report. |
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| Leukodystrophy, adult onset v7.12 | PSAP | Ida Ertmanska reviewed gene: PSAP: Rating: RED; Mode of pathogenicity: None; Publications: 31289144; Phenotypes: Metachromatic leukodystrophy due to SAP-b deficiency, OMIM:249900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.84 | NUS1 | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: NUS1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.31 | NUS1 | Ida Ertmanska Tag Q3_26_expert_review was removed from gene: NUS1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.84 | NUS1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. As this is a proposed 'demotion', an expert-review tag was also added.; to: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.31 | NUS1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. As this is a proposed 'demotion', an expert-review tag was also added.; to: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.35 | PAX6 |
Luke Stuart changed review comment from: Early literature suspected PAX6 as the causative gene for Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation), but direct sequencing repeatedly found no PAX6 mutations in classic Gillespie cases. Linkage analysis in affected families showed the disease trait segregates independently from chromosome 11p markers flanking PAX6 (Glaser et al., 1994; PMID 8188215). |The sausative gene was identified as ITPR1. PAX6 biallelic loss-of-function causes a severe, prenatal/neonatal-onset neurodevelopmental disorder characterised by anophthalmia/microphthalmia and major CNS malformations, including agenesis of the corpus callosum, olfactory bulb aplasia/hypoplasia, brainstem hypoplasia, cortical malformations, and cerebellar dysplasia/hypoplasia; reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities (Glaser et al., 1994, PMID: 7951315; Schmidt-Sidor et al., 2009, PMID: 20054790; Solomon et al., 2010, PMID: 19876904). Thus, biallelic PAX6-related disease is not within scope for the paediatric onset ataxia/ cerebellar anomalies panels. Isolated reports describe heterozygous PAX6 variants associated with neurological manifestations, including ataxia or cerebellar dysfunction: Ticho et al., 2006 (PMID: 17148041): A patient described as having "atypical Gillespie syndrome" presented with mild hand tremor and learning disability but no reported ataxia or structural cerebellar abnormalities on neuroimaging. Sequencing identified a heterozygous PAX6 splice-site variant, IVS2+2T>A. Graziano et al., 2007 (PMID 17595013): described a 9.5-year-old girl with bilateral aniridia, ataxia, and intellectual disability; she carried a de novo heterozygous nonsense variant, PAX6 p.(Trp257Ter). Dansault et al., 2007 (PMID 17417613): In a large family carrying the c.655A>G p.S74G variant, all affected individuals exhibited a mild but consistent cerebellar syndrome. The most severely affected individual had a clear static cerebellar syndrome. MRI findings included hypoplasia of the anterior commissure and absence of the pineal gland in one individual. Despite the consistent neurological phenotype, no specific structural cerebellar abnormalities were identified. Conclusion: Two unrelated PAX6 families with heterozygous variants showed evidence ataxia and/or a cerebellar syndrome phenotype, the latter without any recognisable cerebellar malformation. PAX6 knockout mice delineate a primary role of PAX6 in cerebellar development, though are not known to recapitulate an ataxia phenotype, nor cerebellar phenotype in the context of haploinsufficiency (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)). An amber rating with monoallelic inheritance is proposed.; to: Early literature suspected PAX6 as the causative gene for Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation), but direct sequencing repeatedly found no PAX6 mutations in classic Gillespie cases. Linkage analysis in affected families showed the disease trait segregates independently from chromosome 11p markers flanking PAX6 (Glaser et al., 1994; PMID 8188215). The causative gene was identified as ITPR1. PAX6 biallelic loss-of-function causes a severe, prenatal/neonatal-onset neurodevelopmental disorder characterised by anophthalmia/microphthalmia and major CNS malformations, including agenesis of the corpus callosum, olfactory bulb aplasia/hypoplasia, brainstem hypoplasia, cortical malformations, and cerebellar dysplasia/hypoplasia; reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities (Glaser et al., 1994, PMID: 7951315; Schmidt-Sidor et al., 2009, PMID: 20054790; Solomon et al., 2010, PMID: 19876904). Thus, biallelic PAX6-related disease is not within scope for the paediatric onset ataxia/ cerebellar anomalies panels. Isolated reports describe heterozygous PAX6 variants associated with neurological manifestations, including ataxia or cerebellar dysfunction: Ticho et al., 2006 (PMID: 17148041): A patient described as having "atypical Gillespie syndrome" presented with mild hand tremor and learning disability but no reported ataxia or structural cerebellar abnormalities on neuroimaging. Sequencing identified a heterozygous PAX6 splice-site variant, IVS2+2T>A. Graziano et al., 2007 (PMID 17595013): described a 9.5-year-old girl with bilateral aniridia, ataxia, and intellectual disability; she carried a de novo heterozygous nonsense variant, PAX6 p.(Trp257Ter). Dansault et al., 2007 (PMID 17417613): In a large family carrying the c.655A>G p.S74G variant, all affected individuals exhibited a mild but consistent cerebellar syndrome. The most severely affected individual had a clear static cerebellar syndrome. MRI findings included hypoplasia of the anterior commissure and absence of the pineal gland in one individual. Despite the consistent neurological phenotype, no specific structural cerebellar abnormalities were identified. Conclusion: Two unrelated PAX6 families with heterozygous variants showed evidence ataxia and/or a cerebellar syndrome phenotype, the latter without any recognisable cerebellar malformation. PAX6 knockout mice delineate a primary role of PAX6 in cerebellar development, though are not known to recapitulate an ataxia phenotype, nor cerebellar phenotype in the context of haploinsufficiency (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)). An amber rating with monoallelic inheritance is proposed. |
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| Cystic kidney disease v9.3 | OFD1 | Aakash Joshi changed review comment from: PMCID 11403091 identified one case where the individual presents with a non-syndromic form of renal cysts. Of note the other case reported previously reviewed PMID: 10910455 appears to be a syndromic form, therefore we can only count the one case.; to: PMCID 11403091 identified one case where the individual presents with a non-syndromic form of renal cysts. Of note the other case reported previously reviewed PMID: 10910455 appears to be a syndromic form, therefore we can only count the one case and recommend remain amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | OFD1 | Aakash Joshi reviewed gene: OFD1: Rating: RED; Mode of pathogenicity: None; Publications: PMCID: 11403091; Phenotypes: cystic renal disease; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | COL4A4 | Aakash Joshi changed review comment from: PMCID 10910213 had a cohort of 16 patients with Alport of which 2 unrelated individuals had cystic renal disease. It is unclear whether these individuals would be classed as AD-PKD, but they were noted to not have any extra renal features.; to: PMCID 10910213 had a cohort of 16 patients with Alport of which 2 unrelated individuals had cystic renal disease. It is unclear whether these individuals would be classed as AD-PKD, but they were noted to not have any extra renal features. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | COL4A4 | Aakash Joshi reviewed gene: COL4A4: Rating: RED; Mode of pathogenicity: None; Publications: PMCID 10910213; Phenotypes: cystic renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.3 | CDC73 |
Aakash Joshi gene: CDC73 was added gene: CDC73 was added to Cystic kidney disease. Sources: Literature Mode of inheritance for gene: CDC73 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDC73 were set to PMCID 11748460 Phenotypes for gene: CDC73 were set to multiple renal cysts Penetrance for gene: CDC73 were set to Incomplete Review for gene: CDC73 was set to GREEN Added comment: Monoallelic CDC73 variants can be associated with variable presentation of renal cysts with 15-25% of affected individuals having renal cysts as per GeneReviews. PMCID 11748460 illustrates a case where an individual presented due to renal cysts (however was being concurrently having treatment for a jaw tumour). Sources: Literature |
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| Differences in sex development v4.27 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 36110220 Zidoune H, et al., 2022 Large study of developmental disorders cohort from North Africa. See suppl material for case details. P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 36110220 Zidoune H, et al., 2022 Large study of developmental disorders cohort from North Africa. See suppl material for case details. P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with 46,XY karyotype and variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
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| Childhood interstitial lung disease v1.13 | LAMP3 |
Ida Ertmanska changed review comment from: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a male proband with childhood interstitial lung disease. The individual is a 15-year-old boy born to North African distant consanguineous parents, had no neonatal respiratory distress but presented with a cough and dyspnoea on exertion at the age of 9 years. Chest CT scan showed severe ILD lesions with ground glass opacities and signs of lung fibrosis. Seq method: trio exome sequencing. PMID: 41653023 Keehan et al., 2026 13 participants from 5 unrelated families were identified with biallelic variants in LAMP3 (1 has been reported previously). They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. Probands underwent either exome or genome sequencing, with segregation confirmed by Sanger seq. F1: female proband homozygous for NM_014398.4 LAMP3: c.247del p.(Ile83PhefsTer47); she presented with severe neonatal respiratory failure; serial lung CT studies demonstrate a progression from ground glass opacities (GGO) in early life to fibrotic changes in adolescence. F2: 3 sibs comp het for LAMP3 variants NM_014398:c.38C>A p.(Ala13Glu) and NM_014398:c.1162G>A p.(Gly388Arg). Two older sisters presented with severe neonatal respiratory failure; lung CT imaging that demonstrated GGO and cystic lung disease. In contrast, their younger brother has no history of respiratory symptoms and had unremarkable lung CT imaging at age 14 months. F3: 7 individuals from an extended consanguineous family, homozygous for LAMP3 NM_014398.4:c.862G>A p.(Gly288Arg). 3/7 individuals are clinically asymptomatic, though a chest CT scan revealed areas of GGO and uneven aeration at age 38 yrs. 2 other family members homozygous for the variant were asymptomatic at age 4 and 47 yrs. F4: Male proband, homozygous for an intronic variant in LAMP3 NM_014398.4:c.49+1G>A p.?. He presented with severe neonatal respiratory failure, and lung imaging studies demonstrated diffuse GGO with uneven aeration at age 2 years. F5: Patient described previously in PMID: 40023045 Louvrier et al., 2025. Functional studies in lung epithelial cells demonstrate that some of the LAMP3 variants identified in this cohort cause decreased cell proliferation, induced ER stress, activation of apoptotic pathways, or abnormal protein glycosylation. Variants p.(Gly288Arg) and p.(Gly388Arg) were found to cause abnormalities in the growth of lung A549 epithelial cells. Other functional studies as listed in ClinGen curation: Human Protein Atlas shows protein expression in Lung, Lymph node, and Tonsil tissues only. PMID: 32150563 Dillard et al., 2020 - homozygous for the c.1159G>A (p.Glu387Lys) variant was found to be associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs. PMID: 34161347 Lunding et al., 2021 - Lamp3 knockout mice display regular lung function under basal conditions, aggravated by ovalbumin-induced experimental allergic asthma. The levels of a major hydrophobic protein component of pulmonary surfactant, SP-C, are strongly increased in the lung of Lamp3 knockout mice, and the lipid composition of the bronchoalveolar lavage shows mild but significant changes, resulting in alterations in surfactant functionality. The association between LAMP3 and AR inherited interstitial lung disease has been classified as Definitive in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature; to: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a male proband with childhood interstitial lung disease. The individual is a 15-year-old boy born to North African distant consanguineous parents, had no neonatal respiratory distress but presented with a cough and dyspnoea on exertion at the age of 9 years. Chest CT scan showed severe ILD lesions with ground glass opacities and signs of lung fibrosis. Seq method: trio exome sequencing. PMID: 41653023 Keehan et al., 2026 13 participants from 5 unrelated families were identified with biallelic variants in LAMP3 (1 has been reported previously). They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. Probands underwent either exome or genome sequencing, with segregation confirmed by Sanger seq. F1: female proband homozygous for NM_014398.4 LAMP3: c.247del p.(Ile83PhefsTer47); she presented with severe neonatal respiratory failure; serial lung CT studies demonstrate a progression from ground glass opacities (GGO) in early life to fibrotic changes in adolescence. F2: 3 sibs comp het for LAMP3 variants NM_014398:c.38C>A p.(Ala13Glu) and NM_014398:c.1162G>A p.(Gly388Arg). Two older sisters presented with severe neonatal respiratory failure; lung CT imaging that demonstrated GGO and cystic lung disease. In contrast, their younger brother has no history of respiratory symptoms and had unremarkable lung CT imaging at age 14 months. F3: 7 individuals from an extended consanguineous family, homozygous for LAMP3 NM_014398.4:c.862G>A p.(Gly288Arg). 3/7 individuals are clinically asymptomatic, though a chest CT scan revealed areas of GGO and uneven aeration at age 38 yrs. 2 other family members homozygous for the variant were asymptomatic at age 4 and 47 yrs. F4: Male proband, homozygous for an intronic variant in LAMP3 NM_014398.4:c.49+1G>A p.?. He presented with severe neonatal respiratory failure, and lung imaging studies demonstrated diffuse GGO with uneven aeration at age 2 years. F5: Patient described previously in PMID: 40023045 Louvrier et al., 2025. Functional studies in lung epithelial cells demonstrate that some of the LAMP3 variants identified in this cohort cause decreased cell proliferation, induced ER stress, activation of apoptotic pathways, or abnormal protein glycosylation. Variants p.(Gly288Arg) and p.(Gly388Arg) were found to cause abnormalities in the growth of lung A549 epithelial cells. Other functional studies as listed in ClinGen curation: Human Protein Atlas shows protein expression in Lung, Lymph node, and Tonsil tissues only. PMID: 32150563 Dillard et al., 2020 - homozygous for the c.1159G>A (p.Glu387Lys) variant was found to be associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs. PMID: 34161347 Lunding et al., 2021 - Lamp3 knockout mice display regular lung function under basal conditions, aggravated by ovalbumin-induced experimental allergic asthma. The levels of a major hydrophobic protein component of pulmonary surfactant, SP-C, are strongly increased in the lung of Lamp3 knockout mice, and the lipid composition of the bronchoalveolar lavage shows mild but significant changes, resulting in alterations in surfactant functionality. The association between LAMP3 and AR inherited interstitial lung disease has been classified as Strong in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature |
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| Cystic kidney disease v9.3 | CFAP47 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: CFAP47 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.37 | COL6A3 |
Luke Stuart changed review comment from: COL6A3 is associated with Bethlem myopathy 1C, OMIM #620726; Dystonia 27, OMIM #616411; Ullrich congenital muscular dystrophy 1C, OMIM #620728. As reviewed by Alexander Rossor, Villar-Quiles et al., 2026 (PMID 620728) described Thirty-seven affected individuals from 32 families harbouring biallelic COL6A3 variants. All carried the recurrent c.7447A>G p.(Lys2483Glu) allele either in homozygosity (24 patients) or compound heterozygosity with a second (often truncating) COL6A3 variant (13 patients). Phase was confirmed in 28 cases. Genetic testing was performed via whole-exome sequencing (WES) or whole-genome sequencing (WGS) in 30 patients, and next-generation sequencing (NGS)-based myopathy panel in 7. The cohort demonstrated a consistent distal motor neuropathy-like/neuromyopathic phenotype with neurogenic electrophysiological findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). >70% of the patients showed motor conduction abnormalities, and needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%. All patients carried the recurrent c.7447A>G p.(Lys2483Glu) variant and, therefore, despite the presence of a minority of compound heterozygous patients, it remains unclear whether the observed neuropathy-like phenotype represents a variant-specific effect. In summary, this study provides strong evidence that distal motor neuropathy and neuromyopathy are part of the COL6A3 phenotypic spectrum. A green rating is therefore recommended for the Hereditary neuropathy or pain disorder panel.; to: COL6A3 is associated with Bethlem myopathy 1C, OMIM #620726; Dystonia 27, OMIM #616411; Ullrich congenital muscular dystrophy 1C, OMIM #620728. As reviewed by Alexander Rossor, Villar-Quiles et al., 2026 (PMID 42520849) described Thirty-seven affected individuals from 32 families harbouring biallelic COL6A3 variants. All carried the recurrent c.7447A>G p.(Lys2483Glu) allele either in homozygosity (24 patients) or compound heterozygosity with a second (often truncating) COL6A3 variant (13 patients). Phase was confirmed in 28 cases. Genetic testing was performed via whole-exome sequencing (WES) or whole-genome sequencing (WGS) in 30 patients, and next-generation sequencing (NGS)-based myopathy panel in 7. The cohort demonstrated a consistent distal motor neuropathy-like/neuromyopathic phenotype with neurogenic electrophysiological findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). >70% of the patients showed motor conduction abnormalities, and needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%. All patients carried the recurrent c.7447A>G p.(Lys2483Glu) variant and, therefore, despite the presence of a minority of compound heterozygous patients, it remains unclear whether the observed neuropathy-like phenotype represents a variant-specific effect. In summary, this study provides strong evidence that distal motor neuropathy and neuromyopathy are part of the COL6A3 phenotypic spectrum. A green rating is therefore recommended for the Hereditary neuropathy or pain disorder panel. |
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| Childhood interstitial lung disease v1.13 | LAMP3 | Ida Ertmanska changed review comment from: Comment on list classification: There are now 13 individuals from 5 unrelated families reported in literature with biallelic LAMP3 variants. 4/13 individuals were clinically asymptomatic. However, one of these individuals had signs of lung fibrosis on CT scans. In addition, two individuals were possibly pre-symptomatic - aged 14 months and 4 years at time of report. There is good functional evidence from lung epithelial cells, as well as dog and mouse models, to support this association. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 13 individuals from 5 unrelated families reported in literature with biallelic LAMP3 variants. There are at least 3 unrelated probands that presented with severe neonatal respiratory failure and ground glass opacities seen on lung CT scans. 4/13 individuals were clinically asymptomatic. However, one of these individuals had signs of lung fibrosis on CT scans. In addition, two individuals were possibly pre-symptomatic - aged 14 months and 4 years at time of report. There is good functional evidence from lung epithelial cells, as well as dog and mouse models, to support this association. Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.13 | LAMP3 | Ida Ertmanska Classified gene: LAMP3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.13 | LAMP3 | Ida Ertmanska Added comment: Comment on list classification: There are now 13 individuals from 5 unrelated families reported in literature with biallelic LAMP3 variants. 4/13 individuals were clinically asymptomatic. However, one of these individuals had signs of lung fibrosis on CT scans. In addition, two individuals were possibly pre-symptomatic - aged 14 months and 4 years at time of report. There is good functional evidence from lung epithelial cells, as well as dog and mouse models, to support this association. Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.13 | LAMP3 | Ida Ertmanska Gene: lamp3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.12 | LAMP3 | Ida Ertmanska Publications for gene: LAMP3 were set to 40023045 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.11 | LAMP3 | Ida Ertmanska edited their review of gene: LAMP3: Changed publications to: 32150563, 34161347, 40023045, 41653023 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.11 | LAMP3 |
Ida Ertmanska changed review comment from: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a male proband with childhood interstitial lung disease. The individual is a 15-year-old boy born to North African distant consanguineous parents, had no neonatal respiratory distress but presented with a cough and dyspnoea on exertion at the age of 9 years. Chest CT scan showed severe ILD lesions with ground glass opacities and signs of lung fibrosis. Seq method: trio exome sequencing. PMID: 41653023 Keehan et al., 2026 13 participants from 5 unrelated families were identified with biallelic variants in LAMP3 (1 has been reported previously). They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. Probands underwent either exome or genome sequencing, with segregation confirmed by Sanger seq. F1: female proband homozygous for NM_014398.4 LAMP3: c.247del p.(Ile83PhefsTer47); she presented with severe neonatal respiratory failure; serial lung CT studies demonstrate a progression from ground glass opacities (GGO) in early life to fibrotic changes in adolescence. F2: 3 sibs comp het for LAMP3 variants NM_014398:c.38C>A p.(Ala13Glu) and NM_014398:c.1162G>A p.(Gly388Arg). Two older sisters presented with severe neonatal respiratory failure; lung CT imaging that demonstrated GGO and cystic lung disease. In contrast, their younger brother has no history of respiratory symptoms and had unremarkable lung CT imaging at age 14 months. F3: 7 individuals from an extended consanguineous family, homozygous for LAMP3 NM_014398.4:c.862G>A p.(Gly288Arg). 3/7 individuals are clinically asymptomatic, though a chest CT scan revealed areas of GGO and uneven aeration at age 38 yrs. 2 other family members homozygous for the variant were asymptomatic at age 4 and 47 yrs. F4: Male proband, homozygous for an intronic variant in LAMP3 NM_014398.4:c.49+1G>A p.?. He presented with severe neonatal respiratory failure, and lung imaging studies demonstrated diffuse GGO with uneven aeration at age 2 years. F5: Patient described previously in PMID: 40023045 Louvrier et al., 2025. The association between LAMP3 and AR inherited interstitial lung disease has been classified as Definitive in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature; to: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a male proband with childhood interstitial lung disease. The individual is a 15-year-old boy born to North African distant consanguineous parents, had no neonatal respiratory distress but presented with a cough and dyspnoea on exertion at the age of 9 years. Chest CT scan showed severe ILD lesions with ground glass opacities and signs of lung fibrosis. Seq method: trio exome sequencing. PMID: 41653023 Keehan et al., 2026 13 participants from 5 unrelated families were identified with biallelic variants in LAMP3 (1 has been reported previously). They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. Probands underwent either exome or genome sequencing, with segregation confirmed by Sanger seq. F1: female proband homozygous for NM_014398.4 LAMP3: c.247del p.(Ile83PhefsTer47); she presented with severe neonatal respiratory failure; serial lung CT studies demonstrate a progression from ground glass opacities (GGO) in early life to fibrotic changes in adolescence. F2: 3 sibs comp het for LAMP3 variants NM_014398:c.38C>A p.(Ala13Glu) and NM_014398:c.1162G>A p.(Gly388Arg). Two older sisters presented with severe neonatal respiratory failure; lung CT imaging that demonstrated GGO and cystic lung disease. In contrast, their younger brother has no history of respiratory symptoms and had unremarkable lung CT imaging at age 14 months. F3: 7 individuals from an extended consanguineous family, homozygous for LAMP3 NM_014398.4:c.862G>A p.(Gly288Arg). 3/7 individuals are clinically asymptomatic, though a chest CT scan revealed areas of GGO and uneven aeration at age 38 yrs. 2 other family members homozygous for the variant were asymptomatic at age 4 and 47 yrs. F4: Male proband, homozygous for an intronic variant in LAMP3 NM_014398.4:c.49+1G>A p.?. He presented with severe neonatal respiratory failure, and lung imaging studies demonstrated diffuse GGO with uneven aeration at age 2 years. F5: Patient described previously in PMID: 40023045 Louvrier et al., 2025. Functional studies in lung epithelial cells demonstrate that some of the LAMP3 variants identified in this cohort cause decreased cell proliferation, induced ER stress, activation of apoptotic pathways, or abnormal protein glycosylation. Variants p.(Gly288Arg) and p.(Gly388Arg) were found to cause abnormalities in the growth of lung A549 epithelial cells. Other functional studies as listed in ClinGen curation: Human Protein Atlas shows protein expression in Lung, Lymph node, and Tonsil tissues only. PMID: 32150563 Dillard et al., 2020 - homozygous for the c.1159G>A (p.Glu387Lys) variant was found to be associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs. PMID: 34161347 Lunding et al., 2021 - Lamp3 knockout mice display regular lung function under basal conditions, aggravated by ovalbumin-induced experimental allergic asthma. The levels of a major hydrophobic protein component of pulmonary surfactant, SP-C, are strongly increased in the lung of Lamp3 knockout mice, and the lipid composition of the bronchoalveolar lavage shows mild but significant changes, resulting in alterations in surfactant functionality. The association between LAMP3 and AR inherited interstitial lung disease has been classified as Definitive in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature |
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| Childhood interstitial lung disease v1.11 | LAMP3 |
Ida Ertmanska changed review comment from: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a male proband with childhood interstitial lung disease. The individual is a 15-year-old boy born to North African distant consanguineous parents, had no neonatal respiratory distress but presented with a cough and dyspnoea on exertion at the age of 9 years. Chest CT scan showed severe ILD lesions with ground glass opacities and signs of lung fibrosis. Seq method: trio exome sequencing. PMID: 41653023 Keehan et al,, 2026 13 participants from 5 unrelated families were identified with biallelic variants in LAMP3 (1 has been reported previously). They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. Probands underwent either exome or genome sequencing, with segregation confirmed by Sanger seq. F1: female proband homozygous for NM_014398.4 LAMP3: c.247del p.(Ile83PhefsTer47); she presented with severe neonatal respiratory failure; serial lung CT studies demonstrate a progression from ground glass opacities (GGO) in early life to fibrotic changes in adolescence. F2: 3 sibs comp het for LAMP3 variants NM_014398:c.38C>A p.(Ala13Glu) and NM_014398:c.1162G>A p.(Gly388Arg). Two older sisters presented with severe neonatal respiratory failure; lung CT imaging that demonstrated GGO and cystic lung disease. In contrast, their younger brother has no history of respiratory symptoms and had unremarkable lung CT imaging at age 14 months. F3: 7 individuals from an extended consanguineous family, homozygous for LAMP3 NM_014398.4:c.862G>A p.(Gly288Arg). 3/7 individuals are clinically asymptomatic, though a chest CT scan revealed areas of GGO and uneven aeration at age 38 yrs. 2 other family members homozygous for the variant were asymptomatic at age 4 and 47 yrs. F4: Male proband, homozygous for an intronic variant in LAMP3 NM_014398.4:c.49+1G>A p.?. He presented with severe neonatal respiratory failure, and lung imaging studies demonstrated diffuse GGO with uneven aeration at age 2 years. F5: Patient described previously in PMID: 40023045 Louvrier et al., 2025. The association between LAMP3 and AR inherited interstitial lung disease has been classified as Definitive in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature; to: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a male proband with childhood interstitial lung disease. The individual is a 15-year-old boy born to North African distant consanguineous parents, had no neonatal respiratory distress but presented with a cough and dyspnoea on exertion at the age of 9 years. Chest CT scan showed severe ILD lesions with ground glass opacities and signs of lung fibrosis. Seq method: trio exome sequencing. PMID: 41653023 Keehan et al., 2026 13 participants from 5 unrelated families were identified with biallelic variants in LAMP3 (1 has been reported previously). They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. Probands underwent either exome or genome sequencing, with segregation confirmed by Sanger seq. F1: female proband homozygous for NM_014398.4 LAMP3: c.247del p.(Ile83PhefsTer47); she presented with severe neonatal respiratory failure; serial lung CT studies demonstrate a progression from ground glass opacities (GGO) in early life to fibrotic changes in adolescence. F2: 3 sibs comp het for LAMP3 variants NM_014398:c.38C>A p.(Ala13Glu) and NM_014398:c.1162G>A p.(Gly388Arg). Two older sisters presented with severe neonatal respiratory failure; lung CT imaging that demonstrated GGO and cystic lung disease. In contrast, their younger brother has no history of respiratory symptoms and had unremarkable lung CT imaging at age 14 months. F3: 7 individuals from an extended consanguineous family, homozygous for LAMP3 NM_014398.4:c.862G>A p.(Gly288Arg). 3/7 individuals are clinically asymptomatic, though a chest CT scan revealed areas of GGO and uneven aeration at age 38 yrs. 2 other family members homozygous for the variant were asymptomatic at age 4 and 47 yrs. F4: Male proband, homozygous for an intronic variant in LAMP3 NM_014398.4:c.49+1G>A p.?. He presented with severe neonatal respiratory failure, and lung imaging studies demonstrated diffuse GGO with uneven aeration at age 2 years. F5: Patient described previously in PMID: 40023045 Louvrier et al., 2025. The association between LAMP3 and AR inherited interstitial lung disease has been classified as Definitive in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature |
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| Childhood interstitial lung disease v1.11 | LAMP3 | Ida Ertmanska edited their review of gene: LAMP3: Changed publications to: 40023045, 41653023 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.11 | LAMP3 |
Ida Ertmanska changed review comment from: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a 15 year old boy with childhood interstitial lung disease. PMID: 41653023 Keehan et al,, 2026 13 participants were identified with biallelic variants in LAMP3. They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood The association between LAMP3 and AR inherited interstitial lung disease has been classified as Definitive in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature; to: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a male proband with childhood interstitial lung disease. The individual is a 15-year-old boy born to North African distant consanguineous parents, had no neonatal respiratory distress but presented with a cough and dyspnoea on exertion at the age of 9 years. Chest CT scan showed severe ILD lesions with ground glass opacities and signs of lung fibrosis. Seq method: trio exome sequencing. PMID: 41653023 Keehan et al,, 2026 13 participants from 5 unrelated families were identified with biallelic variants in LAMP3 (1 has been reported previously). They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. Probands underwent either exome or genome sequencing, with segregation confirmed by Sanger seq. F1: female proband homozygous for NM_014398.4 LAMP3: c.247del p.(Ile83PhefsTer47); she presented with severe neonatal respiratory failure; serial lung CT studies demonstrate a progression from ground glass opacities (GGO) in early life to fibrotic changes in adolescence. F2: 3 sibs comp het for LAMP3 variants NM_014398:c.38C>A p.(Ala13Glu) and NM_014398:c.1162G>A p.(Gly388Arg). Two older sisters presented with severe neonatal respiratory failure; lung CT imaging that demonstrated GGO and cystic lung disease. In contrast, their younger brother has no history of respiratory symptoms and had unremarkable lung CT imaging at age 14 months. F3: 7 individuals from an extended consanguineous family, homozygous for LAMP3 NM_014398.4:c.862G>A p.(Gly288Arg). 3/7 individuals are clinically asymptomatic, though a chest CT scan revealed areas of GGO and uneven aeration at age 38 yrs. 2 other family members homozygous for the variant were asymptomatic at age 4 and 47 yrs. F4: Male proband, homozygous for an intronic variant in LAMP3 NM_014398.4:c.49+1G>A p.?. He presented with severe neonatal respiratory failure, and lung imaging studies demonstrated diffuse GGO with uneven aeration at age 2 years. F5: Patient described previously in PMID: 40023045 Louvrier et al., 2025. The association between LAMP3 and AR inherited interstitial lung disease has been classified as Definitive in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature |
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| Childhood interstitial lung disease v1.11 | LAMP3 |
Ida Ertmanska gene: LAMP3 was added gene: LAMP3 was added to Childhood interstitial lung disease. Sources: Literature Q3_26_promote_green tags were added to gene: LAMP3. Mode of inheritance for gene: LAMP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LAMP3 were set to 40023045 Phenotypes for gene: LAMP3 were set to interstitial lung disease specific to childhood, MONDO:0017014 Review for gene: LAMP3 was set to GREEN Added comment: PMID: 40023045 Louvrier et al., 2025 Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a 15 year old boy with childhood interstitial lung disease. PMID: 41653023 Keehan et al,, 2026 13 participants were identified with biallelic variants in LAMP3. They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood The association between LAMP3 and AR inherited interstitial lung disease has been classified as Definitive in ClinGen (Interstitial Lung Disease Expert Panel, 08/18/2026). Sources: Literature |
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| Differences in sex development v4.27 | DMRT1 | Ida Ertmanska Mode of pathogenicity for gene: DMRT1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.26 | DMRT1 | Ida Ertmanska edited their review of gene: DMRT1: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.26 | DMRT1 | Ida Ertmanska changed review comment from: Comment on list classification: Based on available evidence, this gene can be promoted to Green on Differences in sex development at the next update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; to: Comment on list classification: There are now more than 3 cases reported in literature with heterozygous DMRT1 missense variants and gonadal dysgenesis. Based on available evidence, this gene can be promoted to Green on Differences in sex development at the next update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.26 | DMRT1 | Ida Ertmanska Phenotypes for gene: DMRT1 were changed from 46,XY disorders/differences of sex development to 46 XY differences of sex development, MONDO:0020040 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.25 | DMRT1 | Ida Ertmanska Publications for gene: DMRT1 were set to 11870074; 26139570; 24934491; 39936125 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DMRT1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 | Ida Ertmanska commented on gene: DMRT1: Comment on list classification: Based on available evidence, this gene can be promoted to Green on Differences in sex development at the next update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 36110220 Zidoune H, et al., 2022 P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 36110220 Zidoune H, et al., 2022 Large study of developmental disorders cohort from North Africa. See suppl material for case details. P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
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| Differences in sex development v4.24 | DMRT1 | Ida Ertmanska edited their review of gene: DMRT1: Changed publications to: 27711951, 28295047, 31745530, 33057194, 36110220 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 36110220 Zidoune H, et al., 2022 P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
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| Differences in sex development v4.24 | DMRT1 | Ida Ertmanska edited their review of gene: DMRT1: Changed publications to: 27711951, 28295047, 31745530, 33057194 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 33057194 Kaplanis et al., 2021 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
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| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 33057194 Kaplanis et al., 2021 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
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| Differences in sex development v4.24 | DMRT1 | Ida Ertmanska edited their review of gene: DMRT1: Changed publications to: 27711951, 28295047, 31745530 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
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| Differences in sex development v4.24 | DMRT1 | Ida Ertmanska reviewed gene: DMRT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 46 XY differences of sex development, MONDO:0020040; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 | Ida Ertmanska Mode of inheritance for gene: DMRT1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.2 | CFAP47 |
Ida Ertmanska changed review comment from: The association between CFAP47 and X-linked polycystic kidney disease was classified as Disputed on 02/10/2025 by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert panel (see https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da276c83-09e0-428f-a58e-6cd3bf517d00-2025-02-10T170000.000Z). The disputing evidence relates to PMID:39698362 and includes "non-specific genetically heterogenous phenotype, missense variant with no convincing functional data" for the 3 male patients with polycystic kidney disease. 2/3 variants are common in gnomAD v4, with homozygous and numerous hemizygous individuals reported. The curation summary states that "the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance." There is also conflicting functional evidence: PMID: 36571501 describes a knockout 40-week-old mice model with "larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types. However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901)."; to: The association between CFAP47 and X-linked polycystic kidney disease was classified as Disputed on 02/10/2025 by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert panel (see https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da276c83-09e0-428f-a58e-6cd3bf517d00-2025-02-10T170000.000Z). The disputing evidence relates to PMID:39698362 and includes "non-specific genetically heterogenous phenotype, missense variant with no convincing functional data" for the 3 male patients with polycystic kidney disease. 2/3 variants are common in gnomAD v4, with homozygous and numerous hemizygous individuals reported. The curation summary states that "the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance." There is also conflicting functional evidence: PMID: 36571501 describes a knockout 40-week-old mice model with "larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types. However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901)." - consistent with later onset? |
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| Cystic kidney disease v9.2 | CFAP47 |
Ida Ertmanska changed review comment from: The association between CFAP47 and X-linked polycystic kidney disease was classified as Disputed on 02/10/2025 by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert panel (see https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da276c83-09e0-428f-a58e-6cd3bf517d00-2025-02-10T170000.000Z). The disputing evidence relates to PMID:39698362 and includes "non-specific genetically heterogenous phenotype, missense variant with no convincing functional data" for the 3 male patients with polycystic kidney disease. 2/3 variants are common in gnomAD v4, with homozygous and numerous hemizygous individuals reported. The curation summary states that "the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance." There is also conflicting functional evidence: PMID: 36401472, 36571501 describe a knockout 40-week-old mice model with "larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types. However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901)."; to: The association between CFAP47 and X-linked polycystic kidney disease was classified as Disputed on 02/10/2025 by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert panel (see https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_da276c83-09e0-428f-a58e-6cd3bf517d00-2025-02-10T170000.000Z). The disputing evidence relates to PMID:39698362 and includes "non-specific genetically heterogenous phenotype, missense variant with no convincing functional data" for the 3 male patients with polycystic kidney disease. 2/3 variants are common in gnomAD v4, with homozygous and numerous hemizygous individuals reported. The curation summary states that "the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance." There is also conflicting functional evidence: PMID: 36571501 describes a knockout 40-week-old mice model with "larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types. However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901)." |
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| Cystic kidney disease v9.2 | CFAP47 | Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CFAP47. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.2 | CFAP47 |
Ida Ertmanska Tag disputed tag was added to gene: CFAP47. Tag Q3_26_demote_red tag was added to gene: CFAP47. |
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| Cystic kidney disease v9.2 | CFAP47 | Ida Ertmanska changed review comment from: Comment on list classification: Based on conflicting and disputing evidence outlined in the ClinGen curation of evidence linking CFAP47 and X-linked polycystic kidney disease, the rating should be demoted to Red on this panel.; to: Comment on list classification: Based on conflicting and disputing evidence outlined in the ClinGen curation of evidence linking CFAP47 and X-linked polycystic kidney disease, the rating should be demoted to Red on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.2 | CFAP47 | Ida Ertmanska commented on gene: CFAP47: Comment on list classification: Based on conflicting and disputing evidence outlined in the ClinGen curation of evidence linking CFAP47 and X-linked polycystic kidney disease, the rating should be demoted to Red on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.2 | CFAP47 | Ida Ertmanska edited their review of gene: CFAP47: Changed rating: RED; Changed publications to: 39698362; Changed phenotypes to: polycystic kidney disease, MONDO:0020642; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.2 | CFAP47 | Ida Ertmanska commented on gene: CFAP47 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant in trans. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous. However, their heterozygous parents were found to be unaffected. Hence, the MOI should remain BIALLELIC, autosomal or pseudoautosomal, so that variants are not tiered in unaffected carriers.; to: Comment on list classification: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous. However, their heterozygous parents were found to be unaffected. Hence, the MOI should remain BIALLELIC, autosomal or pseudoautosomal, so that variants are not tiered in unaffected carriers. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant in trans. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous. However, their heterozygous parents were found to be unaffected. Hence, the MOI should remain BIALLELIC, autosomal or pseudoautosomal, so that variants are not tiered in unaffected carriers.; to: Comment on list classification: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant in trans. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous. However, their heterozygous parents were found to be unaffected. Hence, the MOI should remain BIALLELIC, autosomal or pseudoautosomal, so that variants are not tiered in unaffected carriers. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska edited their review of gene: FADD: Added comment: Comment on list classification: As reviewed by Nicole Gossan, there are three unrelated patients reported in PMID:37793571 that harboured a FADD missense variant R117H, alongside a somatic variant in trans. Unfortunately, due to technical limitations, the described somatic mutation is currently unlikely to be detected by WGS, and these patients would appear to be heterozygous. However, their heterozygous parents were found to be unaffected. Hence, the MOI should remain BIALLELIC, autosomal or pseudoautosomal, so that variants are not tiered in unaffected carriers.; Changed rating: GREEN; Changed publications to: 18070632, 25794656, 21109225, 37793571; Changed phenotypes to: Immunodeficiency 90 with encephalopathy, functional hyposplenia, and hepatic dysfunction, OMIM:613759, FADD-related immunodeficiency, MONDO:0013408; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Sept 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.107 | FADD | Ida Ertmanska Phenotypes for gene: FADD were changed from Infections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovasuclar malformations, 613759; ALPS-like disease; functional hyposplenism; invasive pneumococcal disease; para-infectious encephalopathy and hepatopathy; cardiovascular malformations; Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction; Diseases of Immune Dysregulation to Immunodeficiency 90 with encephalopathy, functional hyposplenia, and hepatic dysfunction, OMIM:613759; FADD-related immunodeficiency, MONDO:0013408 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.106 | FADD | Ida Ertmanska Publications for gene: FADD were set to 18070632; 17656375; 25794656; 21109225 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.22 | CPOX | Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.22 | CPOX |
Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the appropriate MOI is 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'. However, due to low clinical penetrance of monoallelic variants (<1%), this gene is tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025). |
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| Non-acute porphyrias v2.3 | CPOX | Ida Ertmanska edited their review of gene: CPOX: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.3 | CPOX |
Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; to: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Biallelic variants tend to cause earlier onset and more severe symptoms. Hence, the appropriate MOI is 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'. However, due to low clinical penetrance of monoallelic variants (<1%), this gene is tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025). |
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| Hereditary neuropathy or pain disorder v8.37 | COL6A3 | Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: COL6A3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.34 | UROD | Luke Stuart reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: 3821794, 1905636, 21668429, 20479301, 9211196, 7398998, 7706766; Phenotypes: Porphyria, hepatoerythropoietic, OMIM:176100, Hepatoerythropoietic porphyria, MONDO:0019799; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.17 | UROD | Ida Ertmanska Mode of inheritance for gene: UROD was changed from to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.16 | UROD | Ida Ertmanska Publications for gene: UROD were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.15 | UROD | Ida Ertmanska Phenotypes for gene: UROD were changed from to Porphyria cutanea tarda, OMIM:176100; Porphyria, hepatoerythropoietic, OMIM:176100; hepatoerythropoietic porphyria, MONDO:0019799; porphyria cutanea tarda, MONDO:0015104 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.14 | UROD | Ida Ertmanska reviewed gene: UROD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.19 | PTPRO | Ida Ertmanska Tag watchlist tag was added to gene: PTPRO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.19 | PTPRO | Ida Ertmanska Phenotypes for gene: PTPRO were changed from Nephrotic syndrome, type 6 #614196 to Nephrotic syndrome, type 6, OMIM:614196; nephrotic syndrome, type 6, MONDO:0013619 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.18 | PTPRO | Ida Ertmanska commented on gene: PTPRO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.14 | UROD | Luke Stuart reviewed gene: UROD: Rating: RED; Mode of pathogenicity: None; Publications: 20479301; Phenotypes: Porphyria cutanea tarda OMIM:176100, Hepatoerythropoietic porphyria OMIM:176100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.37 | COL6A3 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: COL6A3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.37 | COL6A3 | Ida Ertmanska Phenotypes for gene: COL6A3 were changed from motor neuropathy; myopathy to Motor peripheral neuropathy, MONDO:0002316 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.36 | COL6A3 | Ida Ertmanska Classified gene: COL6A3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.36 | COL6A3 | Ida Ertmanska Gene: col6a3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.35 | COL6A3 | Ida Ertmanska reviewed gene: COL6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Motor peripheral neuropathy, MONDO:0002316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | PAX3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are now several patients reported with biallelic PAX3 variants and Waardenburg syndrome, type 3. These individuals often present with contractures, ulnar deviation, digit anomalies. Skeletal and limb anomalies are not reported in monoallelic cases. Hence, the mode of inheritance should be changed to "BIALLELIC, autosomal or pseudoautosomal" on Skeletal dysplasia at the next update.; to: Comment on mode of inheritance: There are now several patients reported with biallelic PAX3 variants and Waardenburg syndrome, type 3. These individuals often present with contractures, ulnar deviation, digit anomalies. Skeletal and limb anomalies are not reported in monoallelic cases. Hence, the mode of inheritance should be changed to "BIALLELIC, autosomal or pseudoautosomal" on Skeletal dysplasia at the next update. As this is a 'retraction' of the MONOALLELIC mode of inheritance, an expert-review tag was added, to ensure GMS agreement. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | PAX3 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: PAX3. Tag Q3_26_MOI tag was added to gene: PAX3. |
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| Skeletal dysplasia v10.8 | PAX3 | Ida Ertmanska edited their review of gene: PAX3: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | PAX3 | Ida Ertmanska edited their review of gene: PAX3: Added comment: Comment on mode of inheritance: There are now several patients reported with biallelic PAX3 variants and Waardenburg syndrome, type 3. These individuals often present with contractures, ulnar deviation, digit anomalies. Skeletal and limb anomalies are not reported in monoallelic cases. Hence, the mode of inheritance should be changed to "BIALLELIC, autosomal or pseudoautosomal" on Skeletal dysplasia at the next update.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | PAX3 | Ida Ertmanska changed review comment from: Comment on list classification: There are now 2 cases reported with biallelic PAX3 variants and severe, early-onset "Waardenburg syndrome, type 3", otherwise known as Klein-Waardenburg syndrome, with multiple abnormalities detected on antenatal scans. Based on available evidence, the MOI should remain 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown', with "moi-watchlist" tag added in anticipation of further fetal reports.; to: Comment on list classification: There are now 2 cases reported with biallelic PAX3 variants and severe, early-onset "Waardenburg syndrome, type 3", otherwise known as Klein-Waardenburg syndrome, with multiple abnormalities detected on antenatal scans. Based on available evidence, the MOI should remain 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown', with a "watchlist_moi" tag added in anticipation of further fetal reports. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | PAX3 | Ida Ertmanska Tag watchlist_moi tag was added to gene: PAX3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | PAX3 | Ida Ertmanska commented on gene: PAX3: Comment on list classification: There are now 2 cases reported with biallelic PAX3 variants and severe, early-onset "Waardenburg syndrome, type 3", otherwise known as Klein-Waardenburg syndrome, with multiple abnormalities detected on antenatal scans. Based on available evidence, the MOI should remain 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown', with "moi-watchlist" tag added in anticipation of further fetal reports. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.34 | UROD | Ida Ertmanska Phenotypes for gene: UROD were changed from Porphyria cutanea tarda (Porphyrias with erosive photodermatosis) to Porphyria cutanea tarda, OMIM:176100; Porphyria, hepatoerythropoietic, OMIM:176100; hepatoerythropoietic porphyria, MONDO:0019799; porphyria cutanea tarda, MONDO:0015104 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.22 | UROD | Ida Ertmanska Publications for gene: UROD were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.21 | UROD | Ida Ertmanska Phenotypes for gene: UROD were changed from Porphyria cutanea tarda (Porphyrias with erosive photodermatosis) to Porphyria cutanea tarda, OMIM:176100; Porphyria, hepatoerythropoietic, OMIM:176100; hepatoerythropoietic porphyria, MONDO:0019799; porphyria cutanea tarda, MONDO:0015104 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.3 | UROD | Ida Ertmanska Phenotypes for gene: UROD were changed from Porphyria cutanea tarda OMIM:176100; Porphyria, hepatoerythropoietic OMIM:176100; familial porphyria cutanea tarda MONDO:0008296 to Porphyria cutanea tarda, OMIM:176100; Porphyria, hepatoerythropoietic, OMIM:176100; hepatoerythropoietic porphyria, MONDO:0019799; porphyria cutanea tarda, MONDO:0015104 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.2 | UROD | Ida Ertmanska Publications for gene: UROD were set to 27604308; 9792863 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.1 | UROD | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: UROD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.20 | UROD | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: UROD. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.20 | UROD | Ida Ertmanska reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria cutanea tarda, OMIM:176100, Porphyria, hepatoerythropoietic, OMIM:176100, hepatoerythropoietic porphyria, MONDO:0019799, porphyria cutanea tarda, MONDO:0015104; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.1 | UROD | Ida Ertmanska changed review comment from: Comment on mode of inheritance: As outlined by Sharon Whatley and Luke Stuart, BOTH monoallelic and biallelic UROD variants are associated with non-acute porphyria. While biallelic variants cause more severe, early-onset symptoms, monoallelic variants may also be of clinical significance when accompanied by non-genetic triggers. Hence, the MOI should be changed from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" at the next update.; to: Comment on mode of inheritance: As outlined by Sharon Whatley and Luke Stuart, BOTH monoallelic and biallelic UROD variants are associated with non-acute porphyria. While biallelic variants cause more severe, early-onset cutaneous symptoms, monoallelic variants may also be of clinical significance when accompanied by non-genetic triggers. Hence, the MOI should be changed from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.1 | UROD | Ida Ertmanska reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria cutanea tarda, OMIM:176100, Porphyria, hepatoerythropoietic, OMIM:176100, hepatoerythropoietic porphyria, MONDO:0019799, porphyria cutanea tarda, MONDO:0015104; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.9 | GTF2H4 |
Rhys Dore gene: GTF2H4 was added gene: GTF2H4 was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Research Mode of inheritance for gene: GTF2H4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTF2H4 were set to 40924475 Phenotypes for gene: GTF2H4 were set to xeroderma pigmentosum Penetrance for gene: GTF2H4 were set to unknown Review for gene: GTF2H4 was set to AMBER Added comment: Possible Amber gene. One patient with a clinical diagnosis of XP with compound heterozygous variants in GTF2H4 with support for loss-of-function from a lentiviral assay. Sources: Research |
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| Familial non syndromic congenital heart disease v1.90 | SMAD5 |
Ludmila Volozonoka gene: SMAD5 was added gene: SMAD5 was added to Familial non syndromic congenital heart disease. Sources: Literature Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMAD5 were set to 40619738; 39631055; 42481704 Phenotypes for gene: SMAD5 were set to congenitad heart defect; patent ductus arteriosus; ventricular septal defect; hypoplastic left heart Penetrance for gene: SMAD5 were set to Incomplete Review for gene: SMAD5 was set to GREEN Added comment: PMID: 40619738: SMAD5 variants were identified in 7 individuals from 6 unrelated families, all with CHD. Six individuals had predominantly isolated CHD, while one individual (F1.3) had a multisystem phenotype. Six unique SMAD5 variants were identified: 3 missense variants (p.Thr430Ile, p.Val78Phe, p.Asn361Asp), 2 truncating/LOF variants (p.Ala402Glufs13 and p.Glu261Ter) and 1 copy-number deletion encompassing SMAD5. Four variants were de novo (p.Thr430Ile, p.Val78Phe, p.Asn361Asp and the 5q31.1-q31.2 deletion); p.Ala402Glufs13 was inherited by two affected brothers from a mother who was presumed asymptomatic but was not formally assessed. The authors propose haploinsufficiency as the main mechanism in five of six families, whereas p.Thr430Ile showed functional evidence consistent with a dominant-negative mechanism and was associated with the only multisystem phenotype. PMID: 39631055: Two unrelated patients with pulmonary arterial hypertension (PAH) carried heterozygous SMAD5 missense variants. The second patient carried p.Trp93Arg and had CHD-associated PAH following surgically repaired VSD; her father also had VSD but was not reported to have PAH. PMID: 42481704: Two heterozygous SMAD5 variants were identified in association with PDA. The first, p.Lys82*, was identified in a five-generation family with PDA and segregated with the PDA phenotype. The second, p.Arg70Ile, was identified in one sporadic PDA patient among 174 CHD index cases and was reported as de novo. Sources: Literature |
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| Fetal anomalies v8.7 | SMAD5 | Ludmila Volozonoka reviewed gene: SMAD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 42481704, 39631055, 40619738; Phenotypes: congenitad heart defect, patent ductus arteriosus, ventricular septal defect, hypoplastic left heart; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respiratory ciliopathies including non-CF bronchiectasis v5.4 | CA12 |
Matthew Edwards gene: CA12 was added gene: CA12 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Expert Review Mode of inheritance for gene: CA12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CA12 were set to PMID: 26911677; PMID: 35359895 Phenotypes for gene: CA12 were set to isolated hyperchlorhidrosis Review for gene: CA12 was set to AMBER Added comment: Gene confirmed to cause isolated hyperchlorhidrosis (OMIM#143860), which has been reported to mimic atypical Cystic Fibrosis (CF) - can cause elevated sweat chloride. Some variants associated with gene only cause isolated hyperchlorhidrosis, with no lung involvement, but some associated with broader hentypic spectrum affecting respiratory tract: BESC1 (Bronchiectasis with or without elevated sweat chloride 1). PMID: 26911677 describe two unrelated pedigrees with bi-allelic LOF variants in CA12. One proband: failure to thrive at 2-3 months of age, with sweat chlorides of 82-88mEq/L, with patient mis-diagnosed as having CF rising to 112-16 mEq/L at 9 years of age in one proband. Other phenotypic features: persistent cough, pseudomonas cultures. Other proband: presented at 6 years of age with a history of hyponatremic dehydration and elevated sweat chloride (90-110 mEq/L), with his sister showing a swet chloride of 130mEq/L (iin second pedigree though, there was no lung phenotype). Both sibs were homozygous for a novel missense variant. Obviously limited evidence for patients with lung phenotype currently, but gene should be considered for panel as possible differential in ?CF patients with no CFTR variants detected. Sources: Expert Review |
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| Monogenic short stature v2.9 | IHH |
Melissa Connolly changed review comment from: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of patients with isolated short stature with or without skeletal findings. Sources: Expert Review; to: Gene included in a list of the ten most prevalent genetic causes of isolated short stature in the International guideline on genetic testing of children with Short stature (Supplementary information 4). Text references reports of patients with isolated short stature with or without skeletal findings. Sources: Expert Review |
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| Monogenic short stature v2.9 | FBN1 |
Melissa Connolly changed review comment from: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of SS without typical syndromic features. Hotspots listed as exons 41 and 42 Sources: Expert Review; to: Gene included in a list of the ten most prevalent genetic causes of isolated short stature in the International guideline on genetic testing of children with Short stature (Supplementary information 4). Text references reports of SS without typical syndromic features. Hotspots listed as exons 41 and 42 Sources: Expert Review |
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| Monogenic short stature v2.9 | GHSR | Melissa Connolly changed review comment from: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of patients with low to normal IGF1 or SS with normal serum GH responses to GH stimulation testing.; to: Gene included in a list of the ten most prevalent genetic causes of isolated short stature in the International guideline on genetic testing of children with Short stature (Supplementary information 4). Text references reports of patients with low to normal IGF1 or SS with normal serum GH responses to GH stimulation testing. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | COL2A1 |
Melissa Connolly changed review comment from: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of isolated short stature. Sources: Expert Review; to: Gene included in a list of the ten most prevalent genetic causes of isolated short stature in the International guideline on genetic testing of children with Short stature (Supplementary information 4). Text references reports of isolated short stature. Sources: Expert Review |
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| Monogenic short stature v2.9 | GHSR | Melissa Connolly edited their review of gene: GHSR: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | IHH |
Melissa Connolly gene: IHH was added gene: IHH was added to Monogenic short stature. Sources: Expert Review Mode of inheritance for gene: IHH was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: IHH were set to PMID: 41543979 Phenotypes for gene: IHH were set to ACROCAPITOFEMORAL DYSPLASIA; BRACHYDACTYLY, TYPE A1 Penetrance for gene: IHH were set to Complete Review for gene: IHH was set to GREEN Added comment: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of patients with isolated short stature with or without skeletal findings. Sources: Expert Review |
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| Monogenic short stature v2.9 | GHSR | Melissa Connolly reviewed gene: GHSR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 41543979; Phenotypes: GROWTH HORMONE DEFICIENCY, ISOLATED PARTIAL; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | FBN1 |
Melissa Connolly changed review comment from: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of SS without typical syndromic features. Hotspots listed as exons 41 and 42 Sources: Expert Review; to: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of SS without typical syndromic features. Hotspots listed as exons 41 and 42 Sources: Expert Review |
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| Monogenic short stature v2.9 | FBN1 |
Melissa Connolly gene: FBN1 was added gene: FBN1 was added to Monogenic short stature. Sources: Expert Review Mode of inheritance for gene: FBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBN1 were set to PMID: 41543979 Phenotypes for gene: FBN1 were set to ACROMICRIC DYSPLASIA; GELEOPHYSIC DYSPLASIA 2; STIFF SKIN SYNDROME; WEILL-MARCHESANI SYNDROME 2 Penetrance for gene: FBN1 were set to Complete Mode of pathogenicity for gene: FBN1 was set to Other Review for gene: FBN1 was set to GREEN Added comment: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of SS without typical syndromic features. Hotspots listed as exons 41 and 42 Sources: Expert Review |
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| Monogenic short stature v2.9 | COL2A1 |
Melissa Connolly gene: COL2A1 was added gene: COL2A1 was added to Monogenic short stature. Sources: Expert Review Mode of inheritance for gene: COL2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: COL2A1 were set to PMID: 41543979 Phenotypes for gene: COL2A1 were set to EPIPHYSEAL DYSPLASIA, MULTIPLE, WITH MYOPIA AND CONDUCTIVE DEAFNESS; KNIEST DYSPLASIA; SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA; SPONDYLOEPIMETAPHYSEAL DYSPLASIA, STRUDWICK TYPE; SPONDYLOMETAPHYSEAL DYSPLASIA, ALGERIAN TYPE; SPONDYLOPERIPHERAL DYSPLASIA Penetrance for gene: COL2A1 were set to Complete Review for gene: COL2A1 was set to GREEN Added comment: Gene included in a list of the ten most prevalent genetic causes of isolated short stature (Supplementary information 4). Text references reports of isolated short stature. Sources: Expert Review |
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| Paediatric pseudo-obstruction syndrome v2.8 | MT-TL1 | William Macken reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 41626228, 18226864, 15029099), 16547358); Phenotypes: Intestinal pseudo-obstruction HP:0004389; Mode of inheritance: MITOCHONDRIAL; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | PDE8B |
Rhys Dore gene: PDE8B was added gene: PDE8B was added to Neurodegenerative disorders, adult onset. Sources: Research Mode of inheritance for gene: PDE8B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PDE8B were set to PMID: 20085714, 26475694; 26769607; 31726290; 34022587 Phenotypes for gene: PDE8B were set to striatal degeneration; Parkinsonism; bradykinesia, rigidity; dysarthria Penetrance for gene: PDE8B were set to unknown Review for gene: PDE8B was set to GREEN Added comment: Four families with consistent clinical features of adult onset striatal degeneration and features of Parkinsonism with concomitant predicted loss of function heterozygous variants in PDE8B. A fifth family with a pLOF variant and similar striatal degeneration, but with tremor and dystonia. Sources: Research |
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| Fetal anomalies v8.7 | IFIH1 | Achchuthan Shanmugasundram Tag watchlist was removed from gene: IFIH1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.12 | CTSA | Achchuthan Shanmugasundram Phenotypes for gene: CTSA were changed from Galactosialidosis, 256540 to Brain small vessel disease 6 with leukoencephalopathy, OMIM:621394; cathepsin a-related arteriopathy-strokes-leukoencephalopathy, MONDO:0035551 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.11 | CTSA | Achchuthan Shanmugasundram Publications for gene: CTSA were set to 27159321; 25527826; 28334938; 20301621; 24357685 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.10 | CTSA | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Lauren Turton and Luke Stuart, the MOI should be updated to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.10 | CTSA | Achchuthan Shanmugasundram Mode of inheritance for gene: CTSA was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.9 | CTSA |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: CTSA. Tag Q3_26_MOI tag was added to gene: CTSA. |
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| Hereditary neuropathy or pain disorder v8.35 | DHTKD1 | Ida Ertmanska changed review comment from: Comment on list classification: While there are several patients reported with CMT and DHTKD1 variants (including the recurrent p.Tyr485Ter variant), the variants are of uncertain significance, and evidence for the association is limited. A knock in Dhtkd1 Y486* mouse model showed some signs of neuropathy on histology, but the motor performance was normal in the mutant mice. As reviewed by James Polke, high frequency of LOF variants in gnomAD and lack of a phenotype in carriers of AAKAD can be seen as refuting evidence. Hence, this gene should be downgraded from Green to Amber at the next GMS update.; to: Comment on list classification: While there are several patients reported with CMT and DHTKD1 variants (including the recurrent p.Tyr485Ter variant), the variants are of uncertain significance, and evidence for the association is limited. A knock in Dhtkd1 Y486* mouse model showed some signs of neuropathy on histology, but the motor performance was normal in the mutant mice. As reviewed by James Polke, high frequency of LOF variants in gnomAD and lack of a phenotype in carriers of AAKAD constitutes refuting evidence for this association. Hence, this gene should be downgraded from Green to Red at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.35 | PAX6 | Luke Stuart reviewed gene: PAX6: Rating: AMBER; Mode of pathogenicity: None; Publications: 17148041, 8188215, 7951315, 20054790, 19876904, 17417613, 8213068, 16979618; Phenotypes: Aniridia (OMIM:106210), cerebellar ataxia (MONDO:0000437); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.35 | DHTKD1 |
Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: DHTKD1. Tag Q3_26_demote_red tag was added to gene: DHTKD1. |
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| Hereditary neuropathy or pain disorder v8.35 | DHTKD1 | Ida Ertmanska edited their review of gene: DHTKD1: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | ANAPC1 |
Ida Ertmanska changed review comment from: PMID: 42210937 Huang et al., 2026 Report of a milder case of a 29-year-old man who presented with lifelong sparse, fine scalp hair, bilateral malar erythema, soft fingernails, and dental anomalies (malocclusion with multiple caries). WES identified a heterozygous ANAPC1 (NM_022662.4:c.4907T>C, p.Val1636Ala) variant - 13 hets reported in gnomAD v4 (East Asian pop). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 11 individuals with biallelic ANAPC1 variants from 8 families are included. While short stature is noted in 7/11 patients, severity is not stated. Microcephaly is marked as 'not reported'. Ectodermal dysplasia findings: Poikiloderma (generalized) in 11/11 patients, Sparse hair/eyebrows and/or eyelashes noted in 10/11, and nail dysplasia was seen in 5/11 assessed probands. 10 individuals had juvenile cataracts.; to: PMID: 42210937 Huang et al., 2026 Report of a milder case of a 29-year-old man who presented with lifelong sparse, fine scalp hair, bilateral malar erythema, soft fingernails, and dental anomalies (malocclusion with multiple caries). WES identified a heterozygous ANAPC1 (NM_022662.4:c.4907T>C, p.Val1636Ala) variant - 13 hets reported in gnomAD v4 (East Asian pop). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 11 individuals with biallelic ANAPC1 variants from 8 families are included. While short stature is noted in 7/11 patients, severity is not stated. Microcephaly is marked as 'not reported'. Ectodermal dysplasia findings: Poikiloderma (generalized) in 11/11 patients, Sparse hair/eyebrows and/or eyelashes noted in 10/11, and nail dysplasia was seen in 5/11 assessed probands. 10 individuals had juvenile cataracts. Growth hormone deficiency was diagnosed in 5/10 probands. |
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| Monogenic short stature v2.9 | ANAPC1 | Ida Ertmanska edited their review of gene: ANAPC1: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | ANAPC1 | Ida Ertmanska edited their review of gene: ANAPC1: Changed rating: GREEN; Changed publications to: 31303264, 35664819, 38021400, 42210937 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | ANAPC1 |
Ida Ertmanska changed review comment from: PMID: 42210937 Huang et al., 2026 Report of a milder case of a 29-year-old man who presented with lifelong sparse, fine scalp hair, bilateral malar erythema, soft fingernails, and dental anomalies (malocclusion with multiple caries). WES identified ANAPC1 (NM_022662.4:c.4907T>C, p.Val1636Ala) variant. PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 11 individuals with biallelic ANAPC1 variants from 8 families are included. While short stature is noted in 7/11 patients, severity is not stated. Microcephaly is marked as 'not reported'. Ectodermal dysplasia findings: Poikiloderma (generalized) in 11/11 patients, Sparse hair/eyebrows and/or eyelashes noted in 10/11, and nail dysplasia was seen in 5/11 assessed probands. 10 individuals had juvenile cataracts.; to: PMID: 42210937 Huang et al., 2026 Report of a milder case of a 29-year-old man who presented with lifelong sparse, fine scalp hair, bilateral malar erythema, soft fingernails, and dental anomalies (malocclusion with multiple caries). WES identified a heterozygous ANAPC1 (NM_022662.4:c.4907T>C, p.Val1636Ala) variant - 13 hets reported in gnomAD v4 (East Asian pop). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 11 individuals with biallelic ANAPC1 variants from 8 families are included. While short stature is noted in 7/11 patients, severity is not stated. Microcephaly is marked as 'not reported'. Ectodermal dysplasia findings: Poikiloderma (generalized) in 11/11 patients, Sparse hair/eyebrows and/or eyelashes noted in 10/11, and nail dysplasia was seen in 5/11 assessed probands. 10 individuals had juvenile cataracts. |
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| Monogenic short stature v2.9 | ANAPC1 | Ida Ertmanska reviewed gene: ANAPC1: Rating: RED; Mode of pathogenicity: None; Publications: 38021400, 42210937; Phenotypes: Rothmund-Thomson syndrome, type 1, OMIM:618625, Rothmund-Thomson syndrome type 1, MONDO:0016368; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | PAX6 | Luke Stuart reviewed gene: PAX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 7951315, 19876904, 20054790, 8213068, 16979618; Phenotypes: Corpus callosum, agenesis of (MONDO:0009022); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.9 | RECQL4 | Ida Ertmanska Classified gene: RECQL4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.9 | RECQL4 | Ida Ertmanska Added comment: Comment on list classification: There are numerous patients reported in literature with biallelic RECQL4 variants and Rothmund-Thomson syndrome, with ectodermal dysplasia being a consistent feature (primarily manifesting in poikiloderma, sparse hair/alopecia, sparse eyebrows and eyelashes, sometimes hypoplastic teeth / microdontia). Based on available evidence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.9 | RECQL4 | Ida Ertmanska Gene: recql4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.8 | RECQL4 |
Ida Ertmanska gene: RECQL4 was added gene: RECQL4 was added to Ectodermal dysplasia. Sources: Literature Q3_26_promote_green tags were added to gene: RECQL4. Mode of inheritance for gene: RECQL4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RECQL4 were set to 38021400; 39324487; 40031098; 41628607 Phenotypes for gene: RECQL4 were set to Rothmund-Thomson syndrome, type 2, OMIM:268400; Rothmund-Thomson syndrome type 2, MONDO:0016369 Review for gene: RECQL4 was set to GREEN Added comment: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. Ectodermal dysplasia findings: Poikiloderma (generalized) in 41/43 patients, Sparse hair/eyebrows and/or eyelashes noted in 29/43, and nail dysplasia was seen in 4/7 assessed probands. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teet abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. Sources: Literature |
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| Severe microcephaly v9.32 | RECQL4 |
Ida Ertmanska gene: RECQL4 was added gene: RECQL4 was added to Severe microcephaly. Sources: Literature Mode of inheritance for gene: RECQL4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RECQL4 were set to 38021400; 39324487; 40031098; 41628607 Phenotypes for gene: RECQL4 were set to Rothmund-Thomson syndrome, type 2, OMIM:268400; Rothmund-Thomson syndrome type 2, MONDO:0016369 Review for gene: RECQL4 was set to GREEN Added comment: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teet abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned. Sources: Literature |
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| Monogenic short stature v2.9 | RECQL4 |
Ida Ertmanska edited their review of gene: RECQL4: Added comment: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. PMID: 40031098 Ho et al., 2025 F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected. WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln. F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old. WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*. PMID: 39324487 Kanai et al., 2025 Two Japanese cases with a severe phenotype and biallelic RECQL4 variants. P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES). P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome). PMID: 38021400 Martins et al., 2023 Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'. PMID: 27247962 Suter et al., 2017 Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used. Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teet abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned.; Changed rating: RED; Changed publications to: 38021400, 39324487, 40031098, 41628607; Changed phenotypes to: Rothmund-Thomson syndrome, type 2, OMIM:268400, Rothmund-Thomson syndrome type 2, MONDO:0016369; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Intellectual disability v11.31 | CRIPT | Ida Ertmanska Classified gene: CRIPT as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.31 | CRIPT | Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with developmental delay noted in all patients. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.31 | CRIPT | Ida Ertmanska Gene: cript has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.84 | CRIPT |
Ida Ertmanska changed review comment from: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature; to: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), early-onset seizures (2/4) anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature |
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| Early onset or syndromic epilepsy v9.84 | CRIPT | Ida Ertmanska Classified gene: CRIPT as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.84 | CRIPT | Ida Ertmanska Gene: cript has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.83 | CRIPT | Ida Ertmanska Classified gene: CRIPT as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.83 | CRIPT | Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with early-onset seizures present in 4/6 cases. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.83 | CRIPT | Ida Ertmanska Gene: cript has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.31 | CRIPT | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: CRIPT. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.31 | CRIPT | Ida Ertmanska commented on gene: CRIPT: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with microcephalic dwarfism being a consistent feature. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.31 | CRIPT | Ida Ertmanska Phenotypes for gene: CRIPT were changed from Ida Ertmanska (Genomics England Curator) Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.30 | CRIPT | Ida Ertmanska Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies, 615789 to Ida Ertmanska (Genomics England Curator) Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.29 | CRIPT | Ida Ertmanska Publications for gene: CRIPT were set to 27250922 Leduc et al., 2016 describe a female with biallelic mutations in CRIPT, presenting with short stature, dysmorphic features, microcephaly and hypopigmented macules. They detect a c.8G>A (p.C3Y) missense variant inherited from the mother in exon 1, and a 1,331?bp deletion encompassing exon 1, inherited from the father; 24389050 Shaheen et al., 2014 report 2 cases: they examined cases with Short stature with microcephaly and distinctive facies (OMIM:615789). In a 3 year old boy they identified homozygosity for a 2bp insertion (c.133_134insGG) predicted to cause premature termination (Ala45GlyfsTer87). They also analyzed DNA from the first-cousin parents of a deceased affected male Saudi Arabian infant. The patient was presumed homozygous for a loss of function variant based on the heterozygous status of the parents. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.28 | CRIPT | Ida Ertmanska reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: 24389050, 27250922, 36630262, 37013901; Phenotypes: Rothmund-Thomson syndrome, type 3, OMIM:615789, Rothmund-Thomson syndrome type 3, MONDO:0014347; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.7 | CRIPT | Ida Ertmanska Classified gene: CRIPT as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.7 | CRIPT | Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with features of ectodermal dysplasia. 5/6 probands had sparse hair or alopecia, abnormal teeth were reported in four patients (e.g., conic, delayed), and dystrophic nails were reported in two. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.7 | CRIPT | Ida Ertmanska Gene: cript has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.17 | CRIPT | Ida Ertmanska Classified gene: CRIPT as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.17 | CRIPT | Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with facial rash and poikiloderma being consistent features. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.17 | CRIPT | Ida Ertmanska Gene: cript has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.6 | CRIPT |
Ida Ertmanska changed review comment from: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature; to: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, feet abnormalities, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4), feet anomalies including pes planus, pes calcaneovalgus, and skewfoot |(4/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature |
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| Limb disorders v9.6 | CRIPT | Ida Ertmanska Classified gene: CRIPT as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.6 | CRIPT | Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with toe syndactyly being a consistent feature. In addition, one patient had a proximally placed thumb, and all 6 had feet abnormalities including pes planus, pes calcaneovalgus, and skewfoot. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.6 | CRIPT | Ida Ertmanska Gene: cript has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.6 | CRIPT |
Ida Ertmanska gene: CRIPT was added gene: CRIPT was added to Ectodermal dysplasia. Sources: Literature Q3_26_promote_green tags were added to gene: CRIPT. Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRIPT were set to 24389050; 27250922; 36630262; 37013901 Phenotypes for gene: CRIPT were set to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 Review for gene: CRIPT was set to GREEN Added comment: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature |
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| Limb disorders v9.5 | CRIPT |
Ida Ertmanska gene: CRIPT was added gene: CRIPT was added to Limb disorders. Sources: Literature Q3_26_promote_green tags were added to gene: CRIPT. Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRIPT were set to 24389050; 27250922; 36630262; 37013901 Phenotypes for gene: CRIPT were set to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 Review for gene: CRIPT was set to GREEN Added comment: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature |
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| Early onset or syndromic epilepsy v9.82 | CRIPT |
Ida Ertmanska gene: CRIPT was added gene: CRIPT was added to Early onset or syndromic epilepsy. Sources: Literature Q3_26_promote_green tags were added to gene: CRIPT. Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRIPT were set to 24389050; 27250922; 36630262; 37013901 Phenotypes for gene: CRIPT were set to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 Review for gene: CRIPT was set to GREEN Added comment: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature |
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| Intellectual disability v11.30 | CRIPT |
Ida Ertmanska gene: CRIPT was added gene: CRIPT was added to Intellectual disability. Sources: Literature Q3_26_promote_green tags were added to gene: CRIPT. Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRIPT were set to 24389050; 27250922; 36630262; 37013901 Phenotypes for gene: CRIPT were set to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 Review for gene: CRIPT was set to GREEN Added comment: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature |
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| Pigmentary skin disorders v5.16 | CRIPT |
Ida Ertmanska gene: CRIPT was added gene: CRIPT was added to Pigmentary skin disorders. Sources: Literature Q3_26_promote_green tags were added to gene: CRIPT. Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRIPT were set to 24389050; 27250922; 36630262; 37013901 Phenotypes for gene: CRIPT were set to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 Review for gene: CRIPT was set to GREEN Added comment: PMID: 37013901 Averdunk et al., 2023 Report of 2 probands diagnosed with Rothmund-Thomson syndrome, harbouring biallelic CRIPT variants. P1 - 4yo Moroccan female, homozygous for CRIPT: c.132del, p.Ala45Glnfs*86 P2 - 8yo Romanian male homozygous for CRIPT: c.227G>A, p.(Cys76Tyr) Both patients had facial rash, poikiloderma, sparse hair, short stature, syndactyly of toes, seizures, abnormal teeth, developmental delay, recurrent chest infections; P1 also had cataracts, dystrophic nails, and a proximally placed thumb; only P2 had microcephaly. Also includes literature review of previously reported patients (PMID: 36630262 Akalın et al., 2023; PMID: 27250922 Leduc et al., 2016; PMID: 24389050 Shaheen et al., 2014) - 4 unrelated probands with unique biallelic CRIPT variants: hmz c.133_134insGG, p.(Ala45Glyfs∗82); hmz c.141del p.(Phe47Leufs∗84); comp het c.8G>A p.(Cys3Tyr) & 1,331 bp del exon 1; hmz c.7_8del; p.(Cys3Argfs∗4). 2 individuals were from Saudi Arabia, one from Turkey, and one African American. Phenotype: facial rash (3/4), poikiloderma (2/4), short stature (4/4), sparse hair (3/4), Osteopenia/metaphyseal striations (4/4), dystrophic nails (1/4), syndactyly of toes 4&5 (4/4), proportional microcephaly (4/4), dev delay (4/4), recurrent chest infections (4/4), anemia (3/4), variable retinal defects (4/4), abnormal teeth (2/4), scoliosis (4/4), 11 pairs of ribs (2/4). None of the patients had cataracts. Microcephaly severity: PMID: 27250922 head circumference was 47 cm (Z=−2.7) at 4 yrs. PMID: 24389050: individuals had head circumference of 45 cm (-2.5SD) and 35 cm (-2.7 SD) respectively at time of report. PMID: 36630262 - proband OFC was 44cm at last evaluation (-4.63 SDS). Sources: Literature |
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| Cutaneous photosensitivity with a likely genetic cause v3.20 | DNA2 | Ida Ertmanska changed review comment from: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with early-onset poikiloderma being a consistent feature. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with cutaneous photosensitivity and bullae being consistent features. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.20 | DNA2 | Ida Ertmanska Classified gene: DNA2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.20 | DNA2 | Ida Ertmanska Added comment: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with early-onset poikiloderma being a consistent feature. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.20 | DNA2 | Ida Ertmanska Gene: dna2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.15 | DNA2 | Ida Ertmanska Classified gene: DNA2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.15 | DNA2 | Ida Ertmanska Added comment: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with early-onset poikiloderma being a consistent feature. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.15 | DNA2 | Ida Ertmanska Gene: dna2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.15 | DNA2 | Ida Ertmanska Classified gene: DNA2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.15 | DNA2 | Ida Ertmanska Added comment: Comment on list classification: There are now 8 unrelated patients reported in literature with biallelic DNA2 variants (including a recurrent deep intronic variant) and Rothmund-Thomson syndrome, with congenital bilateral cataracts being a consistent feature. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.15 | DNA2 | Ida Ertmanska Gene: dna2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | DNA2 | Ida Ertmanska changed review comment from: Comment on list classification: As noted for Seckel syndrome, Rothmund-Thomson syndrome cases are not in the scope of this panel, because the short stature is syndromic.; to: Comment on list classification: As noted for Seckel syndrome, Rothmund-Thomson syndrome cases are not in the scope of this panel, because the short stature is syndromic and includes microcephaly. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | DNA2 | Ida Ertmanska commented on gene: DNA2: Comment on list classification: As noted for Seckel syndrome, Rothmund-Thomson syndrome cases are not in the scope of this panel, because the short stature is syndromic. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | DNA2 | Ida Ertmanska reviewed gene: DNA2: Rating: RED; Mode of pathogenicity: None; Publications: 37055165, 40693833; Phenotypes: Rothmund-Thomson syndrome, type 4, OMIM:620819, Seckel syndrome 8, OMIM:615807, Rothmund-Thomson syndrome type 4, MONDO:0970950, Seckel syndrome 8, MONDO:0014350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.19 | DNA2 |
Ida Ertmanska gene: DNA2 was added gene: DNA2 was added to Cutaneous photosensitivity with a likely genetic cause. Sources: Literature Q3_26_promote_green tags were added to gene: DNA2. Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNA2 were set to 37055165; 40693833 Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, type 4, OMIM:620819; Seckel syndrome 8, OMIM:615807; Rothmund-Thomson syndrome type 4, MONDO:0970950; Seckel syndrome 8, MONDO:0014350 Review for gene: DNA2 was set to GREEN Added comment: ROTHMUND-THOMSON SYNDROME: PMID: 37055165 Di Lazzaro Filho et al., 2023 OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges. 6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients. All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant. PMID: 40693833 Ay et al., 2025 Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo. This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026. Sources: Literature |
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| Pigmentary skin disorders v5.14 | DNA2 |
Ida Ertmanska gene: DNA2 was added gene: DNA2 was added to Pigmentary skin disorders. Sources: Literature Q3_26_promote_green tags were added to gene: DNA2. Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNA2 were set to 37055165; 40693833 Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, type 4, OMIM:620819; Seckel syndrome 8, OMIM:615807; Rothmund-Thomson syndrome type 4, MONDO:0970950; Seckel syndrome 8, MONDO:0014350 Review for gene: DNA2 was set to GREEN Added comment: ROTHMUND-THOMSON SYNDROME: PMID: 37055165 Di Lazzaro Filho et al., 2023 OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges. 6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients. All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant. PMID: 40693833 Ay et al., 2025 Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo. This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026. Sources: Literature |
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| Bilateral congenital or childhood onset cataracts v8.14 | DNA2 |
Ida Ertmanska gene: DNA2 was added gene: DNA2 was added to Bilateral congenital or childhood onset cataracts. Sources: Literature Q3_26_promote_green tags were added to gene: DNA2. Mode of inheritance for gene: DNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNA2 were set to 37055165; 40693833 Phenotypes for gene: DNA2 were set to Rothmund-Thomson syndrome, type 4, OMIM:620819; Seckel syndrome 8, OMIM:615807; Rothmund-Thomson syndrome type 4, MONDO:0970950; Seckel syndrome 8, MONDO:0014350 Review for gene: DNA2 was set to GREEN Added comment: ROTHMUND-THOMSON SYNDROME: PMID: 37055165 Di Lazzaro Filho et al., 2023 OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges. 6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients. All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant. PMID: 40693833 Ay et al., 2025 Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo. This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026. Sources: Literature |
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| Severe microcephaly v9.28 | DNA2 |
Ida Ertmanska changed review comment from: ROTHMUND-THOMSON SYNDROME: PMID: 37055165 Di Lazzaro Filho et al., 2023 OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges. 6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients. All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant. PMID: 40693833 Ay et al., 2025 Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo.; to: ROTHMUND-THOMSON SYNDROME: PMID: 37055165 Di Lazzaro Filho et al., 2023 OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges. 6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients. All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant. PMID: 40693833 Ay et al., 2025 Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo. This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026. |
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| Severe microcephaly v9.28 | DNA2 | Ida Ertmanska edited their review of gene: DNA2: Changed publications to: 37055165, 40693833 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.28 | DNA2 |
Ida Ertmanska changed review comment from: PMID: 37055165 Di Lazzaro Filho et al., 2023 Summary from OMIM 620819: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.; to: ROTHMUND-THOMSON SYNDROME: PMID: 37055165 Di Lazzaro Filho et al., 2023 OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges. 6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients. All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant. PMID: 40693833 Ay et al., 2025 Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo. |
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| Severe microcephaly v9.28 | DNA2 |
Ida Ertmanska changed review comment from: PMID: 37055165 Di Lazzaro Filho et al., 2023; to: PMID: 37055165 Di Lazzaro Filho et al., 2023 Summary from OMIM 620819: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges. |
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| Severe microcephaly v9.28 | DNA2 | Ida Ertmanska reviewed gene: DNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37055165; Phenotypes: Rothmund-Thomson syndrome, type 4, OMIM:620819, Seckel syndrome 8, OMIM:615807, Rothmund-Thomson syndrome type 4, MONDO:0970950, Seckel syndrome 8, MONDO:0014350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.9 | CTSA |
Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from three pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). This variant has been described across a number of CARASAL cohorts from varying backgrounds, though most patients described to-date are of European origin. Hervé et al., 2012 (PMID 23175731): Identified a chromosome 20q13 region linked to a leukoencephalopathy phenotype in two French sisters. A later publication reported that this family was subsequently confirmed to carry the recurrent CTSA p.Arg325Cys variant (personal communication with the authors; 2026 report). Bugiani et al., 2016 (PMID 27664989): First description of CARASAL in two Dutch kindreds. Haplotype analysis revealed a shared region of 1,145 kb on chromosome 20q13 suggesting a common ancestral origin, and the c.973C>T p.(Arg325Cys) variant (identified via exome sequencing) segregated with disease. The authors proposed that the introduced cysteine residue may alter protein folding, although SDS-PAGE experiments did not support this. Based on increased cathepsin A precursor protein, astrocytic endothelin-1 (ET-1) accumulation, increased premyelinating oligodendrocyte progenitors, and reduced myelin basic protein in patient white matter, they proposed that impaired ET-1 degradation contributes to vasculopathy and defective oligodendrocyte maturation. This mechanism is inferential and has not been experimentally validated. Hwang et al., 2017 (PMID 28702507): Reported an additional British patient with CARASAL heterozygous for CTSA c.973C>T p(Arg325Cys). Analysis of the informative marker D20S838 suggested a common genetic ancestry with the previously reported Dutch families. Budhdeo et al., 2022 (PMID 35904593): Described two further affected individuals, one of Chinese ancestry and one Brazilian individual of Italian origin, in who underwent exome sequencing and targeted Sanger sequencing, respectively. These cases expanded the ethnic distribution of CARASAL beyond the previously reported Dutch, British, and French families. Haplotype data were not available. Cerfontaine et al., 2026 (PMID 41908989): Reported 21 affected individuals (including 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys), 4 affected obligate carriers) a from three Dutch pedigrees, including some overlap with the original 2016 Bugiani discovery cohort. The recurrent CTSA p.Arg325Cys variant was described as a Dutch founder variant and segregated with disease across multiple large pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. Yoon et al., 2023 (case report, accessed at:https://www.jns-journal.com/article/S0022-510X(23)01466-1/fulltext): Reported a Korean patient presenting with cognitive decline and leukodystrophy on brain imaging. Sequencing of a lysosomal disease panel identified heterozygous CTSA c.973C>T (p.Arg325Cys). Population data:CTSA c.973C>T (p.Arg325Cys) is present in gnomAD v4 in one heterozygous individual (European non-Finnish ancestry), with no homozygotes observed (overall allele frequency 6.2 × 10^-7). In silico data: AlphaMissense predicts the variant to be likely benign. In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Despite lacking functional evidence supporting variant pathogenicity and a yet-to-be determined disease mechanism, segregation and enrichment in relevant disease cohorts is convincing across multiple ethnic backgrounds. Thus a green rating is reiterated, with monoallelic inheritance. |
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| Skeletal dysplasia v10.8 | HPGD |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: HPGD. Tag Q3_26_MOI tag was added to gene: HPGD. |
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| Skeletal dysplasia v10.8 | HPGD | Ida Ertmanska changed review comment from: Comment on mode of inheritance: Out of more than 70 Primary hypertrophic osteoarthropathy (PHO) patients reported in literature, only 3 of them habroured monoallelic HPGD variants and were reported to have a mild phenotype. Some het carrier family members in recessive pedigrees presented with mild digital clubbing. Based on available evidence, the heterozygous cases are not in scope of the Skeletal dysplasia panel, and the mode of inheritance should be changed to BIALLELIC only.; to: Comment on mode of inheritance: Out of more than 70 Primary hypertrophic osteoarthropathy (PHO) patients reported in literature, only 3 of them habroured monoallelic HPGD variants and only direct HPGD/SLCO2A1 Sanger sequencing was used in these studies. Some het carrier family members in recessive pedigrees presented with mild digital clubbing - not in scope of this panel. Based on available literature, the evidence for a dominant association is limited and the mode of inheritance should be changed to BIALLELIC only. An expert_review tag was added to ensure GMS agreement regarding this change. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | HPGD |
Ida Ertmanska changed review comment from: PMID: 35813463 Lu et al., 2022 Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia). Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants. PMID: 26135126 Yuan et al., 2015 Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only. Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing. Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4. PMID: 18500342 Uppal et al., 2008 Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. Only HPGD was sequenced, using PCR amplification. HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.; to: PMID: 35813463 Lu et al., 2022 Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. All patients were negative for SLCO2A1 mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia). Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants. PMID: 26135126 Yuan et al., 2015 Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only. Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing. They were negative for SLCO2A1 mutations. Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4. PMID: 18500342 Uppal et al., 2008 Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. Only HPGD was sequenced, using PCR amplification. HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026. |
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| Skeletal dysplasia v10.8 | HPGD |
Ida Ertmanska changed review comment from: PMID: 35813463 Lu et al., 2022 Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia). Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants. PMID: 26135126 Yuan et al., 2015 Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only. Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing. Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4. PMID: 18500342 Uppal et al., 2008 Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.; to: PMID: 35813463 Lu et al., 2022 Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia). Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants. PMID: 26135126 Yuan et al., 2015 Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only. Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing. Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4. PMID: 18500342 Uppal et al., 2008 Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. Only HPGD was sequenced, using PCR amplification. HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026. |
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| Skeletal dysplasia v10.8 | HPGD |
Ida Ertmanska changed review comment from: PMID: 35813463 Lu et al., 2022 Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia). Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants. PMID: 26135126 Yuan et al., 2015 Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4. Variant HPGD:c.488G>A, p.Arg163His has MAF = 0.00002673 (African population), no hmz. PMID: 18500342 Uppal et al., 2008 Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.; to: PMID: 35813463 Lu et al., 2022 Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. Direct HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia). Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants. PMID: 26135126 Yuan et al., 2015 Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Seq method: Sanger seq of HPGD only. Heterozygous individuals (P8 and P9) were het for the c.310_311del variant. Both individuals had digital clubbing. P8 also showed pachydermia, while P9 presented with periostosis, joint swelling, and hyperhidrosis. The authors acknowledge the possiblity that a second undetectable null mutation may have been missed in the het patients, due to limitations of Sanger sequencing. Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4. PMID: 18500342 Uppal et al., 2008 Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026. |
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| Skeletal dysplasia v10.8 | HPGD | Ida Ertmanska commented on gene: HPGD: Comment on mode of inheritance: Out of more than 70 Primary hypertrophic osteoarthropathy (PHO) patients reported in literature, only 3 of them habroured monoallelic HPGD variants and were reported to have a mild phenotype. Some het carrier family members in recessive pedigrees presented with mild digital clubbing. Based on available evidence, the heterozygous cases are not in scope of the Skeletal dysplasia panel, and the mode of inheritance should be changed to BIALLELIC only. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | HPGD |
Ida Ertmanska changed review comment from: PMID: 35813463 Lu et al., 2022 Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia). Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants. PMID: 26135126 Yuan et al., 2015 Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4. Variant HPGD:c.488G>A, p.Arg163His has MAF = 0.00002673 (African population), no hmz. PMID: 18500342 Uppal et al., 2008 Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026.; to: PMID: 35813463 Lu et al., 2022 Study of 12 Chinese Primary hypertrophic osteoarthropathy (PHO) patients from 11 families. HPGD sequencing revealed 7 different mutations. The recurrent mutation c.310_311delCT were found in all eleven patients. 11/12 individuals had biallelic HPGD mutations. The heterozygous patient P1 habroured the c.310_311delCT variant and had a mild phenotype (mild finger clubbing, periostosis, and mild pachydermia). Digital clubbing and periostosis were the most common shared features, with pachydermia, hyperhidrosis, and joint swelling also frequently reported. The study's literature reviews states that only 2/77 PHO patients reported in literature had monoallelic HPGD variants. PMID: 26135126 Yuan et al., 2015 Study of 2 sibs and 7 sporadic cases with primary hypertrophic osteoarthropathy. A recurrent c.310_311delCT mutation was identified in all patients, of which six were homozygous, two were heterozygous, and one was compound heterozygous with this mutation and a novel heterozygous missense mutation c.488G>A (p.R163H). Variant HPGD:c.310_311del, p.Leu104Alafs*3 has MAF = 0.0004281 (East Asian pop), with no hmz reported in gnomAD v4. Variant HPGD:c.488G>A, p.Arg163His has MAF = 0.00002673 (African population), no hmz. PMID: 18500342 Uppal et al., 2008 Report of 4 families with PHO, probands harboured biallelic HPGD variants. Some heterozygous family members were also noted to have mild digital clubbing. 2/4 families are from North Pakistan, both probands were homozygous for p.Ala140Pro and confirmed to be distantly related on haplotype analysis. The affected individuals in other 2 families, 1 described as Polish and non-consanguineous, harboured homozygous putative LoF variants. HPGD is only associated with recessive disease entities in OMIM (Cranioosteoarthropathy, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, ?Digital clubbing, isolated congenital) and G2P (HPGD-related cranioosteoarthropathy, biallelic_autosomal) - resources accessed 10th Sept 2026. |
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| Skeletal dysplasia v10.8 | HPGD | Ida Ertmanska reviewed gene: HPGD: Rating: GREEN; Mode of pathogenicity: None; Publications: 18500342, 26135126, 35813463; Phenotypes: ?Digital clubbing, isolated congenital , OMIM:119900, Cranioosteoarthropathy, OMIM:259100, Hypertrophic osteoarthropathy, primary, autosomal recessive 1, OMIM:259100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.81 | SLC12A5 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: SLC12A5. Tag Q3_26_MOI tag was added to gene: SLC12A5. |
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| Early onset or syndromic epilepsy v9.81 | SLC12A5 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. An expert_review rating was added to ensure agreement on this change.; to: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. An expert_review rating was added to ensure GMS agreement on this change. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.81 | SLC12A5 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only.; to: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. An expert_review rating was added to ensure agreement on this change. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.81 | SLC12A5 | Ida Ertmanska commented on gene: SLC12A5: Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.81 | SLC12A5 |
Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 24668262 Puskarjov et al., 2014 Study analyzed 378 (266 unrelated) patients with seizure disorders. Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported). PMID: 24928908 Kahle et al., 2014 Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article. Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes. PMID: 31104500 Till et al., 2019 Male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy. WES detected a het SLC12A5:c.1348G>A, p.Val450Ile variant. 15 hets reported in gnomAD v4. [Article mostly in Hungarian] SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports: PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5 PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H) PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant); to: MONOALLELIC REPORTS: PMID: 24668262 Puskarjov et al., 2014 Study analyzed 378 (266 unrelated) patients with seizure disorders. Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported). PMID: 24928908 Kahle et al., 2014 Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article. Variant p.R1049C has 33 hets and MAF = 0.0001537 in gnomAD v4, no homozygotes. PMID: 31104500 Till et al., 2019 Male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy. WES detected a het SLC12A5:c.1348G>A, p.Val450Ile variant. 15 hets reported in gnomAD v4. [Article mostly in Hungarian] SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports: PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5 PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H) PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant) |
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| Early onset or syndromic epilepsy v9.81 | SLC12A5 |
Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 24668262 Puskarjov et al., 2014 Study analyzed 378 (266 unrelated) patients with seizure disorders. Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported). PMID: 24928908 Kahle et al., 2014 Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article. Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes. SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports: PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5 PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H) PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant); to: MONOALLELIC REPORTS: PMID: 24668262 Puskarjov et al., 2014 Study analyzed 378 (266 unrelated) patients with seizure disorders. Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported). PMID: 24928908 Kahle et al., 2014 Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article. Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes. PMID: 31104500 Till et al., 2019 Male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy. WES detected a het SLC12A5:c.1348G>A, p.Val450Ile variant. 15 hets reported in gnomAD v4. [Article mostly in Hungarian] SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports: PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5 PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H) PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant) |
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| Early onset or syndromic epilepsy v9.81 | SLC12A5 | Ida Ertmanska edited their review of gene: SLC12A5: Changed publications to: 24668262, 24928908, 28477354, 38660387, 42033187 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.81 | SLC12A5 |
Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 24668262 Puskarjov et al., 2014 Study analyzed 378 (266 unrelated) patients with seizure disorders. Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported). PMID: 24928908 Kahle et al., 2014 Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article. Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes.; to: MONOALLELIC REPORTS: PMID: 24668262 Puskarjov et al., 2014 Study analyzed 378 (266 unrelated) patients with seizure disorders. Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported). PMID: 24928908 Kahle et al., 2014 Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article. Variant p.R1049C has MAF = 0.0001537 in gnomAD v4 and no homozygotes. SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports: PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5 PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H) PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant) |
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| Retinal disorders v9.19 | LRPAP1 |
Nicky Cronbach gene: LRPAP1 was added gene: LRPAP1 was added to Retinal disorders. Sources: Literature Mode of inheritance for gene: LRPAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRPAP1 were set to PMID: 23830514; 33951325; 31607522; 39444998 Phenotypes for gene: LRPAP1 were set to Non-syndromic high myopia; early-onset high myopia; pathological myopia Penetrance for gene: LRPAP1 were set to Complete Review for gene: LRPAP1 was set to GREEN Added comment: Sources: Literature |
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| Early onset or syndromic epilepsy v9.81 | SLC12A5 | Ida Ertmanska reviewed gene: SLC12A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24668262, 24928908; Phenotypes: {Epilepsy, idiopathic generalized, susceptibility to, 14}, OMIM:616685, Developmental and epileptic encephalopathy 34, OMIM:616645; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.81 | SLC1A2 | Ida Ertmanska Publications for gene: SLC1A2 were set to 27476654; 28777935; 23934111; 9180080; 28915517; 27445142 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.80 | SLC1A2 |
Ida Ertmanska Tag Q3_26_expert_review was removed from gene: SLC1A2. Tag Q3_26_MOI was removed from gene: SLC1A2. |
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| Intellectual disability v11.29 | SLC1A2 | Ida Ertmanska commented on gene: SLC1A2: Comment on mode of inheritance: There are at least 16 individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with normal intelligence / mild ID. Hence, the mode of inheritance should remain as MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.29 | SLC1A2 | Ida Ertmanska reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9180080, 28915517, 40174554; Phenotypes: Developmental and epileptic encephalopathy 41, OMIM:617105, developmental and epileptic encephalopathy, 41, MONDO:0014916; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.80 | SLC1A2 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with vision loss. A supportive mouse model showed that knockout slc1a2-/- mice develop severe epilepsy. Functional effects of the 2 recessive variants were assessed as LoF in HEK293T and COS-7 cell transfection experiments (PMID: 40174554). Hence, the mode of inheritance should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are at least 16 individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with vision loss. A supportive mouse model showed that knockout slc1a2-/- mice develop severe epilepsy. Functional effects of the 2 recessive variants were assessed as LoF in HEK293T and COS-7 cell transfection experiments (PMID: 40174554). Hence, the mode of inheritance should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.80 | SLC1A2 | Ida Ertmanska commented on gene: SLC1A2: Comment on mode of inheritance: There are numerous individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with vision loss. A supportive mouse model showed that knockout slc1a2-/- mice develop severe epilepsy. Functional effects of the 2 recessive variants were assessed as LoF in HEK293T and COS-7 cell transfection experiments (PMID: 40174554). Hence, the mode of inheritance should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.80 | SLC1A2 | Ida Ertmanska edited their review of gene: SLC1A2: Changed publications to: 9180080, 28915517, 40174554 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.80 | SLC1A2 |
Ida Ertmanska changed review comment from: PMID: 40174554 Kovermann et al., 2025 Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517). Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. 1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants had neurodevelopmental impairment and epilepsy with seizure onset between 2 and 4 years of age, had normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. Both had severe vision loss, and one had bilateral hypoplasia of the optic nerves. SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026.; to: PMID: 40174554 Kovermann et al., 2025 Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517). Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. 1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants had neurodevelopmental impairment and epilepsy with seizure onset between 2 and 4 years of age, had normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. Both had severe vision loss, and one had bilateral hypoplasia of the optic nerves. In contrast, 2 individuals heterozygous for F249Sfs∗17 and A432D variants (also in the LoF category) had a more severe NDD phenotype without vision loss. Functional: PMID: 9180080 Tanaka et al., 1997 - homozygous Slc1a2−/− mice have severe epilepsy with neurodegeneration resulting from reduced glial L-Glu uptake. SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026. |
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| Early onset or syndromic epilepsy v9.80 | SLC1A2 |
Ida Ertmanska changed review comment from: PMID: 40174554 Kovermann et al., 2025 Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517). Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. 1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants "either displayed normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. However, both had severe vision loss, and one had bilateral hypoplasia of the optic nerves." SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026.; to: PMID: 40174554 Kovermann et al., 2025 Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517). Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. 1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants had neurodevelopmental impairment and epilepsy with seizure onset between 2 and 4 years of age, had normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. Both had severe vision loss, and one had bilateral hypoplasia of the optic nerves. SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026. |
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| Early onset or syndromic epilepsy v9.80 | SLC1A2 |
Ida Ertmanska changed review comment from: PMID: 40174554 Kovermann et al., 2025 Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517). Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. 1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants "either displayed normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. However, both had severe vision loss, and one had bilateral hypoplasia of the optic nerves."; to: PMID: 40174554 Kovermann et al., 2025 Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517). Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. 1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants "either displayed normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. However, both had severe vision loss, and one had bilateral hypoplasia of the optic nerves." SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026. |
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| Early onset or syndromic epilepsy v9.80 | SLC1A2 |
Ida Ertmanska changed review comment from: PMID: 40174554 Kovermann et al., 2025 Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517). Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. 1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study.; to: PMID: 40174554 Kovermann et al., 2025 Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517). Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. 1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants "either displayed normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. However, both had severe vision loss, and one had bilateral hypoplasia of the optic nerves." |
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| Early onset or syndromic epilepsy v9.80 | SLC1A2 | Ida Ertmanska reviewed gene: SLC1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28915517, 40174554; Phenotypes: Developmental and epileptic encephalopathy 41, OMIM:617105, developmental and epileptic encephalopathy, 41, MONDO:0014916; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.80 | SLC1A2 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: SLC1A2. Tag Q3_26_MOI tag was added to gene: SLC1A2. |
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| Early onset or syndromic epilepsy v9.80 | CLCN3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.29 | CLCN3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | CLCN3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association.; to: Comment on mode of inheritance: There is currently only 1 recessive pedigree reported in literature where 2 sibs with a neurodevelopmental disorder with seizures and brain abnormalities harboured a homozygous frameshift CLCN3 variant. More than 20 individuals have been reported with an NDD and harbouring heterozygous missense variants in CLCN3. Hence, the mode of inheritance should be changed to MONOALLELIC only, until more evidence emerges for the BIALLELIC association. An expert_review tag was added to ensure GMS is in agreement on this demotion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.80 | CLCN3 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CLCN3. Tag Q3_26_MOI tag was added to gene: CLCN3. |
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| Intellectual disability v11.29 | CLCN3 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CLCN3. Tag Q3_26_MOI tag was added to gene: CLCN3. |
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| Early onset or syndromic epilepsy v9.80 | CLCN3 | Ida Ertmanska reviewed gene: CLCN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34186028; Phenotypes: ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517, Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.29 | CLCN3 | Ida Ertmanska reviewed gene: CLCN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34186028; Phenotypes: ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517, Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | CLCN3 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CLCN3. Tag Q3_26_MOI tag was added to gene: CLCN3. |
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| Fetal anomalies v8.7 | CLCN3 | Ida Ertmanska reviewed gene: CLCN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34186028; Phenotypes: ?Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517, Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.80 | STXBP1 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: STXBP1. Tag Q3_26_MOI tag was added to gene: STXBP1. |
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| Intellectual disability v11.29 | STXBP1 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: STXBP1. Tag Q3_26_MOI tag was added to gene: STXBP1. |
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| Early onset or syndromic epilepsy v9.80 | STXBP1 | Ida Ertmanska Phenotypes for gene: STXBP1 were changed from Developmental and epileptic encephalopathy 4, OMIM:612164 to Developmental and epileptic encephalopathy 4, OMIM:612164; developmental and epileptic encephalopathy, 4, MONDO:0012812 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.29 | STXBP1 | Ida Ertmanska reviewed gene: STXBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31855252; Phenotypes: Developmental and epileptic encephalopathy 4, OMIM:612164, developmental and epileptic encephalopathy, 4, MONDO:0012812; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.79 | STXBP1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 reported pedigree where individuals with Lennox-Gastaut syndrome harboured biallelic STXBP1 variants. All other reported individuals have monoallelic variants. Hence, there is not enough evidence for a BIALLELIC association, and the MOI should be reverted to MONOALLELIC only.; to: Comment on mode of inheritance: To date, there is only 1 reported pedigree where individuals with Lennox-Gastaut syndrome harboured biallelic STXBP1 variants. All other reported individuals have monoallelic variants. Hence, there is not enough evidence for a BIALLELIC association, and the MOI should be reverted to MONOALLELIC only. An expert-review tag was added to ensure GMS agreement on this demotion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.79 | STXBP1 | Ida Ertmanska reviewed gene: STXBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31855252; Phenotypes: Developmental and epileptic encephalopathy 4, OMIM:612164, developmental and epileptic encephalopathy, 4, MONDO:0012812; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.29 | NUS1 |
Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: NUS1. Tag Q3_26_MOI tag was added to gene: NUS1. |
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| Early onset or syndromic epilepsy v9.79 | NUS1 |
Ida Ertmanska Tag Q3_26_demote_amber was removed from gene: NUS1. Tag Q3_26_MOI tag was added to gene: NUS1. |
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| Early onset or syndromic epilepsy v9.79 | NUS1 | Ida Ertmanska Phenotypes for gene: NUS1 were changed from Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082 to ?Congenital disorder of glycosylation, type 1aa, OMIM:617082; Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.29 | NUS1 | Ida Ertmanska Phenotypes for gene: NUS1 were changed from Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082 to ?Congenital disorder of glycosylation, type 1aa, OMIM:617082; Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.28 | NUS1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC.; to: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. As this is a proposed 'demotion', an expert-review tag was also added. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.78 | NUS1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC.; to: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. As this is a proposed 'demotion', an expert-review tag was also added. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.28 | NUS1 |
Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: NUS1. Tag Q3_26_expert_review tag was added to gene: NUS1. |
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| Early onset or syndromic epilepsy v9.78 | NUS1 |
Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: NUS1. Tag Q3_26_expert_review tag was added to gene: NUS1. |
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| Early onset or syndromic epilepsy v9.78 | NUS1 | Ida Ertmanska reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066056; Phenotypes: ?Congenital disorder of glycosylation, type 1aa, OMIM:617082, Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.28 | NUS1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous NUS1 variant, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC.; to: Comment on mode of inheritance: To date, there is only 1 family reported in literature with 2 sibs harbouring a homozygous missense variant in NUS1, diagnosed with a congenital disorder of glycosylation (with features of congenital scoliosis, profound psychomotor retardation, refractory epilepsy and macular lesions showing retinitis pigmentosa). Some supporting evidence from a knockout mouse was also provided. However, there is still insufficient evidence reported to warrant a Green rating for the BIALLELIC mode of inheritance. Hence, the MOI should be reverted to MONOALLELIC. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.28 | NUS1 | Ida Ertmanska reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25066056; Phenotypes: ?Congenital disorder of glycosylation, type 1aa, OMIM:617082, Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in IFIH1. Heterozygous gain-of-function variants are thought to result in Aicardi-Goutieres syndrome (autoimmune disorder), while putative LoF variants have been reported in patients with inborn errors of immunity and early-onset IBD. Many cases harbour relatively common hypomorphic variants, which slightly impair MDA5 activity and increase susceptibility to infections with incomplete penetrance. True recessive cases are relatively rare, with only 6 individuals reported with biallelic rare variants in IFIH1 (PMIDs: 29018476; 34185153). Nonetheless, MOI should remain BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.; to: Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in IFIH1. Heterozygous gain-of-function variants are thought to result in Aicardi-Goutieres syndrome (autoimmune disorder), while putative LoF variants have been reported in patients with inborn errors of immunity and early-onset IBD. Many cases harbour relatively common hypomorphic variants, which slightly impair MDA5 activity and increase susceptibility to infections with incomplete penetrance. True recessive cases are relatively rare, with only 6 individuals reported with biallelic rare variants in IFIH1 (PMIDs: 29018476; 34185153). Based on available evidence, MOI should remain BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 | Ida Ertmanska commented on gene: IFIH1: Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in IFIH1. Heterozygous gain-of-function variants are thought to result in Aicardi-Goutieres syndrome (autoimmune disorder), while putative LoF variants have been reported in patients with inborn errors of immunity and early-onset IBD. Many cases harbour relatively common hypomorphic variants, which slightly impair MDA5 activity and increase susceptibility to infections with incomplete penetrance. True recessive cases are relatively rare, with only 6 individuals reported with biallelic rare variants in IFIH1 (PMIDs: 29018476; 34185153). Nonetheless, MOI should remain BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 | Ida Ertmanska edited their review of gene: IFIH1: Changed phenotypes to: Immunodeficiency 95, OMIM:619773, immunodeficiency 95, MONDO:0030692, Aicardi-Goutieres syndrome 7, OMIM:615846, Aicardi-Goutieres syndrome 7, MONDO:0014367 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 | Ida Ertmanska edited their review of gene: IFIH1: Changed publications to: 28606988, 28716935, 29018476, 34185153, 34726731, 38757311 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 |
Ida Ertmanska changed review comment from: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34185153 Cananzi et al., 2021 Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported. Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis. Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 29018476 Zaki et al. 2017 Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. IFIH1 is associated with AD Aicardi-Goutieres syndrome 7, OMIM:615846, AD Singleton-Merten syndrome 1, OMIM:182250, and AR Immunodeficiency 95, OMIM:619773 (Accessed 9th Sept 2026).; to: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34185153 Cananzi et al., 2021 Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported. Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis. Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 29018476 Zaki et al. 2017 Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. IFIH1 is associated with AD Aicardi-Goutieres syndrome 7, OMIM:615846, AD Singleton-Merten syndrome 1, OMIM:182250, and AR Immunodeficiency 95, OMIM:619773 (Accessed 9th Sept 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 |
Ida Ertmanska changed review comment from: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34185153 Cananzi et al., 2021 Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported. Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis. Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 29018476 Zaki et al. 2017 Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.; to: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34185153 Cananzi et al., 2021 Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported. Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis. Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 29018476 Zaki et al. 2017 Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. IFIH1 is associated with AD Aicardi-Goutieres syndrome 7, OMIM:615846, AD Singleton-Merten syndrome 1, OMIM:182250, and AR Immunodeficiency 95, OMIM:619773 (Accessed 9th Sept 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 |
Ida Ertmanska changed review comment from: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34185153 Cananzi et al., 2021 Cohort of 42 Very Early Onset IBD probands. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported. Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 29018476 Zaki et al. 2017 Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.; to: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34185153 Cananzi et al., 2021 Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported. Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis. Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 29018476 Zaki et al. 2017 Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 | Ida Ertmanska edited their review of gene: IFIH1: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 | Ida Ertmanska edited their review of gene: IFIH1: Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 |
Ida Ertmanska changed review comment from: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.; to: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34185153 Cananzi et al., 2021 Cohort of 42 Very Early Onset IBD probands. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported. Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 29018476 Zaki et al. 2017 Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 |
Ida Ertmanska changed review comment from: PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.; to: PMID: 38757311 Najm et al., 2024 Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted. PMID: 34726731 Chen et al., 2021 Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES. P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N. P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported. The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis. PMID: 28716935 Asgari et al., 2017 Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported. 1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom. Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar). PMID: 28606988 Lamborn et al., 2017 5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections. The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES. Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 | Ida Ertmanska edited their review of gene: IFIH1: Changed rating: RED; Changed publications to: 34726731, 28716935, 28606988; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | IFIH1 | Ida Ertmanska reviewed gene: IFIH1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 95, OMIM:619773, immunodeficiency 95, MONDO:0030692; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.33 | LBR | Ida Ertmanska Phenotypes for gene: LBR were changed from ?Reynolds syndrome 613471; Greenberg skeletal dysplasia 215140; Pelger-Huet anomaly 169400; Pelger-Huet anomaly with mild skeletal anomalies 618019 to Pelger-Huet anomaly, OMIM:169400; Greenberg skeletal dysplasia, OMIM:215140; Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, OMIM:618019; ?Reynolds syndrome, OMIM:613471 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.32 | LBR |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: LBR. Tag Q3_26_MOI tag was added to gene: LBR. |
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| Likely inborn error of metabolism v9.32 | LBR | Ida Ertmanska changed review comment from: Comment on mode of inheritance: Pelger-Huet anomaly, seen in carriers of heterozygous LBR variants, does not usually cause any symptoms and thus it is considered a benign condition. Hence, the mode of inheritance should be changed to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. An expert_review tag has been added to ensure GMS agreement with this demotion.; to: Comment on mode of inheritance: Pelger-Huet anomaly, seen in numerous carriers of heterozygous LBR variants, does not usually cause any symptoms and thus it is considered a benign condition. There is also one patient reported with a het LBR variant and Reynolds syndrome. However, the variant is present in homozygous state in gnomAD, and its significance is hard to determine. Hence, the mode of inheritance should be changed to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. An expert_review tag has been added to ensure GMS agreement with this demotion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.32 | LBR | Ida Ertmanska edited their review of gene: LBR: Changed publications to: 12118250, 19468205, 20522425 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.32 | LBR |
Ida Ertmanska changed review comment from: MONOALLELIC CASES Reynolds syndrome: PMID: 20522425 Gaudy-Marqueste et al., 2010 76-year-old Caucasian woman with Reynolds syndrome (primary biliary cholangitis and limited cutaneous systemic sclerosis). She was het for LBR c.1114C>T; p.Arg372Cys - AF in gnomAD is 0.0002441, with 2 homozygotes reported. Pelger-Huet anomaly (PHA) is considered to be a benign disorder in most instances, as individuals with PHA are typically healthy. It is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape and structure. See PMID: 12118250 Hoffmann et al., 2002. LBR is associated with AR regressive spondylometaphyseal dysplasia (Moderate, 2023) and AR Greenberg dysplasia (Moderate, 2023) in ClinGen. LBR is linked to AR Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, AR Greenberg skeletal dysplasia, AD Pelger-Huet anomaly, and putatively linked to AD ?Reynolds syndrome in OMIM (accessed 9th Sept 2026).; to: MONOALLELIC CASES Reynolds syndrome: PMID: 20522425 Gaudy-Marqueste et al., 2010 76-year-old Caucasian woman with Reynolds syndrome (primary biliary cholangitis and limited cutaneous systemic sclerosis). She was het for LBR c.1114C>T; p.Arg372Cys - AF in gnomAD is 0.0002441, with 2 homozygotes reported. Pelger-Huet anomaly (PHA) is considered to be a benign disorder in most instances, as individuals with PHA are typically healthy. It is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape and structure. See PMID: 12118250 Hoffmann et al., 2002 and PMID: 19468205 Speeckaert et al., 2009. LBR is associated with AR regressive spondylometaphyseal dysplasia (Moderate, 2023) and AR Greenberg dysplasia (Moderate, 2023) in ClinGen. LBR is linked to AR Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, AR Greenberg skeletal dysplasia, AD Pelger-Huet anomaly, and putatively linked to AD ?Reynolds syndrome in OMIM (accessed 9th Sept 2026). |
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| Likely inborn error of metabolism v9.32 | LBR |
Ida Ertmanska changed review comment from: MONOALLELIC CASES Reynolds syndrome: PMID: 20522425 Gaudy-Marqueste et al., 2010 76-year-old Caucasian woman with Reynolds syndrome (primary biliary cholangitis and limited cutaneous systemic sclerosis). She was het for LBR c.1114C>T; p.Arg372Cys - AF in gnomAD is 0.0002441, with 2 homozygotes reported. Pelger-Huet anomaly (PHA) is considered to be a benign disorder in most instances, as individuals with PHA are typically healthy. It is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape and structure. PMID: 12118250 Hoffmann et al., 2002. LBR is associated with AR regressive spondylometaphyseal dysplasia (Moderate, 2023) and AR Greenberg dysplasia (Moderate, 2023) in ClinGen. LBR is linked to AR Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, AR Greenberg skeletal dysplasia, AD Pelger-Huet anomaly, and putatively linked to AD ?Reynolds syndrome in OMIM (accessed 9th Sept 2026).; to: MONOALLELIC CASES Reynolds syndrome: PMID: 20522425 Gaudy-Marqueste et al., 2010 76-year-old Caucasian woman with Reynolds syndrome (primary biliary cholangitis and limited cutaneous systemic sclerosis). She was het for LBR c.1114C>T; p.Arg372Cys - AF in gnomAD is 0.0002441, with 2 homozygotes reported. Pelger-Huet anomaly (PHA) is considered to be a benign disorder in most instances, as individuals with PHA are typically healthy. It is an inherited blood condition in which the nuclei of several types of white blood cells (neutrophils and eosinophils) have unusual shape and structure. See PMID: 12118250 Hoffmann et al., 2002. LBR is associated with AR regressive spondylometaphyseal dysplasia (Moderate, 2023) and AR Greenberg dysplasia (Moderate, 2023) in ClinGen. LBR is linked to AR Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, AR Greenberg skeletal dysplasia, AD Pelger-Huet anomaly, and putatively linked to AD ?Reynolds syndrome in OMIM (accessed 9th Sept 2026). |
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| Likely inborn error of metabolism v9.32 | LBR | Ida Ertmanska commented on gene: LBR: Comment on mode of inheritance: Pelger-Huet anomaly, seen in carriers of heterozygous LBR variants, does not usually cause any symptoms and thus it is considered a benign condition. Hence, the mode of inheritance should be changed to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. An expert_review tag has been added to ensure GMS agreement with this demotion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.32 | LBR | Ida Ertmanska edited their review of gene: LBR: Changed publications to: 12118250, 20522425 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.32 | LBR | Ida Ertmanska reviewed gene: LBR: Rating: GREEN; Mode of pathogenicity: None; Publications: 20522425; Phenotypes: Pelger-Huet anomaly, OMIM:169400, Greenberg skeletal dysplasia, OMIM:215140, Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly, OMIM:618019, ?Reynolds syndrome, OMIM:613471; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.9 | CTSA |
Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from two pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from three pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate. |
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| Leukodystrophy, adult onset v7.9 | CTSA |
Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers, from two pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys)). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 affected obligate carriers, from two pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate. |
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| Leukodystrophy, adult onset v7.9 | CTSA |
Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers, from two pedigrees. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate. |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.20 | ATP6V1E1 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ATP6V1E1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.20 | ATP6V1E1 | Ida Ertmanska Tag Q3_26_promote_green was removed from gene: ATP6V1E1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.20 | ATP6V1E1 | Ida Ertmanska Classified gene: ATP6V1E1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.20 | ATP6V1E1 | Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated individuals reported in literature with biallelic ATP6V1E1 variants and syndromic cutis laxa, with variable features including congenital heart defects, hypotonia, aortic dilation, contractures, and more. Hence, this gene can be promoted to Green on Ehlers Danlos syndrome with a likely monogenic cause. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.20 | ATP6V1E1 | Ida Ertmanska Gene: atp6v1e1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.19 | ATP6V1E1 |
Ida Ertmanska gene: ATP6V1E1 was added gene: ATP6V1E1 was added to Ehlers Danlos syndrome with a likely monogenic cause. Sources: Literature Q3_26_promote_green tags were added to gene: ATP6V1E1. Mode of inheritance for gene: ATP6V1E1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATP6V1E1 were set to 27023906; 28065471 Phenotypes for gene: ATP6V1E1 were set to Cutis laxa, autosomal recessive, type IIC, OMIM:617402; autosomal recessive cutis laxa type 2C, MONDO:0027462 Review for gene: ATP6V1E1 was set to GREEN Added comment: PMID: 27023906 Alazami et al., 2016 Study of a cohort of 40 families with inherited connective tissue disorders. Family 5 - Saudi brothers homozygous for ATP6V1E1:c.634C>T, p.Arg212Trp (2 alleles reported in gnomAD v4.1.1., no hom). Seq method: WES followed by WGS (ATP6V1E1 variant missed by WES due to poor coverage). The sibs presented with cutis laxa, dysmorphic facial features, strabismus, congenital heart defects, nephrocalcinosis, midline cleft palate. Pregnancy was complicated by oligohydramnios and hydronephrosis. Parents are first cousins, unaffected. PMID: 28065471 Van Damme et al., 2018 Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). Both families with ATP6V1E1 variants were consanguineous, and the probands were homozygous for a ATP6V1E1 variant each: c.383T>C, p.Leu128Pro in PI & c.634C>T, p.Arg212Trp in PII. Variant p.Leu128Pro not found in gnomAD v4.1.1. Patient phenotypes: cutis laxa 2/2, severe hypotonia 1 (1 not determined), cardiac abnormalities 2/2, aortic dilation 1/2, contractures 1/2; seizures and MRI abnormalities were not determined. All parents reported to be unaffected. This gene is associated with Cutis laxa, autosomal recessive, type IIC, OMIM:617402 in OMIM, and ATP6V1E1-related cutis laxa (biallelic_autosomal) in G2P with a Strong confidence level (resources accessed 9th Sept 2026). Sources: Literature |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.18 | ATP6V1A | Ida Ertmanska Phenotypes for gene: ATP6V1A were changed from Cutis laxa, autosomal recessive, type IID, OMIM:617403 to Cutis laxa, autosomal recessive, type IID, OMIM:617403; autosomal recessive cutis laxa type 2D, MONDO:0027451 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.78 | ATP6V1A |
Ida Ertmanska commented on gene: ATP6V1A: Comment on mode of inheritance: There are more than 30 individuals reported in literature with heterozygous de novo missense variants in ATP6V1A and a Developmental and epileptic encephalopathy (including early onset seizures in at least 28 cases). There are also 6 probands reported with biallelic ATP6V1A variants, of which only 2 presented with seizures. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. As this is a demotion of the BIALLELIC MOI, an expert_review tag was also added. |
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| Early onset or syndromic epilepsy v9.78 | ATP6V1A | Ida Ertmanska Phenotypes for gene: ATP6V1A were changed from Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403 to Developmental and epileptic encephalopathy 93, OMIM:618012; developmental and epileptic encephalopathy 93, MONDO:0020632 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.77 | ATP6V1A | Ida Ertmanska edited their review of gene: ATP6V1A: Changed phenotypes to: Developmental and epileptic encephalopathy 93, OMIM:618012, developmental and epileptic encephalopathy 93, MONDO:0020632 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.77 | ATP6V1A | Ida Ertmanska Publications for gene: ATP6V1A were set to 29668857; 28065471 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | ATP6V1A |
Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: ATP6V1A. Tag Q3_26_expert_review tag was added to gene: ATP6V1A. |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.17 | ATP6V1A | Ida Ertmanska edited their review of gene: ATP6V1A: Changed publications to: 28065471, 33320377, 40225911 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.17 | ATP6V1A |
Ida Ertmanska changed review comment from: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).; to: BIALLELIC CASES: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys). PMID: 28065471 Van Damme et al., 2017 Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys. Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum). All parents reported to be unaffected. MONOALLELIC CASES: PMID: 40225911 Ma et al., 2024 Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu). Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient. ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026). |
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| Early onset or syndromic epilepsy v9.76 | ATP6V1A |
Ida Ertmanska changed review comment from: BIALLELIC CASES: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys). PMID: 28065471 Van Damme et al., 2017 Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys. Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum). MONOALLELIC CASES: PMID: 40225911 Ma et al., 2024 Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu). Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient. ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026).; to: BIALLELIC CASES: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys). PMID: 28065471 Van Damme et al., 2017 Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys. Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum). All parents reported to be unaffected. MONOALLELIC CASES: PMID: 40225911 Ma et al., 2024 Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu). Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient. ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026). |
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| Early onset or syndromic epilepsy v9.76 | ATP6V1A | Ida Ertmanska edited their review of gene: ATP6V1A: Changed publications to: 28065471, 33320377, 40225911 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | ATP6V1A |
Ida Ertmanska changed review comment from: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).; to: BIALLELIC CASES: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. No seizures noted in either family. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys). PMID: 28065471 Van Damme et al., 2017 Report of 5 families with syndromic cutis laxa and biallelic variants in ATP6V1E1 (2 families from Iran and Kuwait) and ATP6V1A (3 families from Germany, Turkey, and Pakistan). 2/3 families with ATP6V1A variants were consanguineous, and the probands were homozygous for the same ATP6V1A variant: c.215G>A, p.Gly72Asp. The German proband was homozygous for c.1012C>T, p.Arg338Cys. Patient phenotypes: cutis laxa 3/3, severe hypotonia 3/3, cardiac abnormalities 3/3, aortic dilation 1/3, seizures 2/2 (1 not determined), contractures 1/3, MRI abnormalities (3/3 - 1 mild with an anatomical variant of the cavum septum pellucidum). MONOALLELIC CASES: PMID: 40225911 Ma et al., 2024 Literature review of 31 previously reported cases with monoallelic de novo missense ATP6V1A variants and a Developmental and epileptic encephalopathy (DEE), plus two new cases with de novo heterozygous variants: c.1061G>T/p.(Trp354Leu) and c.746C>T/p.(Pro249Leu). Common patient features from literature review: seizures (28/33), global developmental delay (29/33), hypotonia in infancy (24/33). Seizures mostly started within first 3 years of life (23/33). Most patients had no speech or poor language skills, which correlated with seizure severity. Brain MRI of 22 patients showed: hypomyelination in 13 patients, mild brain and cerebellar atrophy in 13 patients, thin corpus callosum in 4 patients, and bilateral lateral ventricle body broaden in one patient. ATP6V1A is associated with Cutis laxa, autosomal recessive, type IID and AD Developmental and epileptic encephalopathy 93 in OMIM (Accessed 9th Sept 2026). |
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| Early onset or syndromic epilepsy v9.76 | ATP6V1A | Ida Ertmanska reviewed gene: ATP6V1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33320377; Phenotypes: Cutis laxa, autosomal recessive, type IID, OMIM:617403, autosomal recessive cutis laxa type 2D, MONDO:0027451; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.17 | ATP6V1A |
Ida Ertmanska changed review comment from: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys).; to: PMID: 33320377 Vogt et al., 2021 Report of three affected individuals with a severely progeroid form of congenital cutis laxa with generalized muscular hypotonia (2 sibs from a Hungarian family and a boy from a consanguineous Turkish family). Method: WES. Male proband from Family A showed generalized cutis laxa with redundant skin and muscular hypotonia, progeroid appearance, bilateral leg weakness, bilateral contractures of his hips and knees; muscle biopsy revealed increased connective and fatty tissue, increased variability of fiber size, rounded fibers, some central nuclei and degenerating fibers with vacuoles. CK was strongly elevated. He died at 8 days of age due to cardiac and respiratory failure. His brother was similarly affected, but his symptoms improved and he is alive at 17 years old. Although weak muscle tone and thin skin remained, he has normal cognition and attends high school. Proband was comp het for ATP6V1A variants: c.317 T > C, p.(Leu106Ser) & c.1513_1514del, p.(Asp505*) Male proband from Family B presented at birth with generalized muscular hypotonia, retrognathia and severe cutis laxa. He had normal speech and cognitive development. General muscular hypotonia and weakness were noted at age 4 years. Cranial MRI showed a cortical atrophy. His CK was elevated. His muscle weakness improved over time - he had normal endurance and muscle strength without any progression or loss of motor functions at 15yo. He was found to be homozygous for ATP6V1A: c.284 T > A, p.(Met95Lys). |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.17 | ATP6V1A | Ida Ertmanska reviewed gene: ATP6V1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33320377; Phenotypes: Cutis laxa, autosomal recessive, type IID, OMIM:617403, autosomal recessive cutis laxa type 2D, MONDO:0027451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.9 | CTSA |
Luke Stuart changed review comment from: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate.; to: CTSA is associated with autosmal dominant Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394, accessed 08/2026), also referred to as Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL). CARASAL is caused by a single recurrent heterozygous CTSA variant, c.973C>T p.(Arg325Cys) (updated nomenclature NM_000308.4:c.919C>T p.(Arg307Cys). In a CARASAL case series comprising two families harboring heterozygous CTSA c.973C>T p.(Arg325Cys) identified by exome sequencing, haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 in affected individuals suggesting a common ancestor (Bugiani et al., 2016, PMID 27664989). N.B. all patients described to date are of European ancestry, aside from one Chinese proband described by Budheo et al., 2022 (PMID 35904593). Cerfontaine et al., 2026 (PMID 41908989) described a large CARASAL case series comprising 16 patients heterozygous for CTSA c.973C>T p.(Arg325Cys) and 4 obligate carriers. The authors characterised CARASAL's defining leukodystrophy signature as a combination of very high, early, and progressive confluent white matter hyperintensity (particularly in the pons) with relatively mild associated atrophic changes. Pontine confluent white matter hyperintensities (WMHs) were present in 100% of patients (16/16), and extensive confluent WMHs present in 15/16 patients with MRI. The precise mechanism by which the CTSA c.973C>T p.(Arg325Cys) causes disease is largely unknown (Bugiani et al., 2016, PMID 27664989) In conclusion, CARASAL, characterised by a prominent adult-onset leukodystrophy phenotype, is caused by a single recurrent heterozygous missense CTSA variant. Thus monoallelic inheritance is appropriate. |
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| Leukodystrophy, adult onset v7.9 | CTSA | Luke Stuart reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35904593, 41908989, 27664989; Phenotypes: Brain small vessel disease 6 with leukoencephalopathy (OMIM:621394), cathepsin a-related arteriopathy-strokes-leukoencephalopathy (MONDO:0035551); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.18 | APOE | Ida Ertmanska commented on gene: APOE: Comment on mode of inheritance: There are numerous patients with proteinuria and glomerulopathy linked to APOE variants. However, most of these patients harbour monoallelic rare variants, together with a homozygous APOE2 risk allele. There seems to be only 1 case reported with biallelic rare APOE missense variants, inherited from unaffected parents (PMID: 35119017). Hence, the mode of inheritance should stay MONOALLELIC, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.18 | APOE |
Ida Ertmanska changed review comment from: PMID: 24570682 Kawanishi et al., 2013 Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor. Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium. Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68. Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region. PMID: 29692990 Fukunaga et al., 2018 Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was homozygous for APOE2 allele and heterozygous for APOE p.Ser197Cys rare variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1). PMID: 31874799 Saito et al., 2020; to: PMID: 24570682 Kawanishi et al., 2013 Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor. Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium. Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68. Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region. PMID: 29692990 Fukunaga et al., 2018 Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was homozygous for APOE2 allele and heterozygous for APOE p.Ser197Cys rare variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1). PMID: 35119017 Li et al., 2021 Report of a 28-year-old man who presented with severe proteinuria (4+), hyperlipidemia (serum total cholesterol, 7.09 mmol/L, low-density lipoprotein cholesterol [LDL-C], 6.39 mmol/L), edema of both legs, and normal serum albumin level; he was diagnosed with lipoprotein glomerulopathy. Renal biopsy revealed lipoprotein thrombi in the glomeruli. Immunofluorescence staining revealed APOE-positive deposits, particularly within the glomeruli. He was comp het for APOE variants: c.127C > T (p.Arg43Cys) & c.149G > A (p.Arg50His) - in trans, inherited from unaffected het parents. Both variants are rare in gnomAD, with no homozygotes reported. PMID: 35950048 Koshino et al., 2022 Case report: 28-year-old Japanese man with mild proteinuria (+1) and hematuria, harbouring het APOE variant p.(Ser197Cys) and homozygous apoE2/2 risk allele. Kidney biopsy revealed mesangial proliferation, mesangial matrix expansion, and segmental spike lesion; EM showed massive deposits with various electron densities, the glomerular basement membrane (GBM) structure was partly degenerated by these deposits. |
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| Proteinuric renal disease v6.18 | APOE |
Ida Ertmanska changed review comment from: PMID: 24570682 Kawanishi et al., 2013 Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor. Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium. Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68. Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region. PMID: 29692990 Fukunaga et al., 2018 Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was heterozygous for APOE p.Ser197Cys variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1). PMID: 31874799 Saito et al., 2020; to: PMID: 24570682 Kawanishi et al., 2013 Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor. Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium. Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68. Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region. PMID: 29692990 Fukunaga et al., 2018 Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was homozygous for APOE2 allele and heterozygous for APOE p.Ser197Cys rare variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1). PMID: 31874799 Saito et al., 2020 |
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| Proteinuric renal disease v6.18 | APOE | Ida Ertmanska reviewed gene: APOE: Rating: GREEN; Mode of pathogenicity: None; Publications: 24570682, 29692990; Phenotypes: Lipoprotein glomerulopathy, OMIM:611771, lipoprotein glomerulopathy, MONDO:0012725; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | TBX6 | Luke Stuart reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25564734, 33058178, 23335591, 12620991; Phenotypes: Spondylocostal dysostosis 5 (OMIM #122600), spondylocostal dysostosis 5 (MONDO:0007389); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | TBX6 | Luke Stuart reviewed gene: TBX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PIMD: 25564734, 33058178, 23335591; Phenotypes: Spondylocostal dysostosis 5 (OMIM #122600), spondylocostal dysostosis 5 (MONDO:0007389); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.35 | OGDH | Achchuthan Shanmugasundram Classified gene: OGDH as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.35 | OGDH | Achchuthan Shanmugasundram Gene: ogdh has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.34 | OGDH | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated amber with current evidence.; to: Comment on list classification: There is one patient reported with neuropathy. Although there is functional evidence available for the reported variant from Drosophila model, only locomotion defects was reported as the phenotype in the publication, which support association with ataxia. This gene should be rated red with current evidence on the neuropathy panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.34 | OGDH | Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | OGDH | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated red with current evidence.; to: Comment on list classification: There is one patient and functional evidence from Drosophila models available. But, the evidence from drosophila model only supports locomotion defects and not any eye phenotypes. Hence, this gene should be rated red with current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.34 | OGDH | Achchuthan Shanmugasundram Classified gene: OGDH as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.34 | OGDH | Achchuthan Shanmugasundram Gene: ogdh has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.33 | OGDH | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated red with current evidence.; to: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated amber with current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.33 | OGDH | Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.25 | VPS13C | Eleanor Williams commented on gene: VPS13C | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | VPS13C | Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype Parkinson disease 23, early onset, OMIM:616840 accessed on 7th Sept 2026 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.15 | VPS13C | Eleanor Williams Phenotypes for gene: VPS13C were changed from Parkinson disease 23, early onset, OMIM:616840; autosomal recessive early-onset Parkinson disease 23, MONDO:0014796 to Parkinson disease 23, early onset, OMIM:616840; autosomal recessive early-onset Parkinson disease 23, MONDO:0014796 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.14 | VPS13C | Eleanor Williams Phenotypes for gene: VPS13C were changed from Parkinson disease 23, autosomal recessive, early onset, OMIM:616840 to Parkinson disease 23, early onset, OMIM:616840; autosomal recessive early-onset Parkinson disease 23, MONDO:0014796 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.13 | VPS13C | Eleanor Williams Publications for gene: VPS13C were set to 26942284; 28137300; 28862745 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.33 | MRPS34 |
Alexander Rossor gene: MRPS34 was added gene: MRPS34 was added to Hereditary neuropathy or pain disorder. Sources: Other Mode of inheritance for gene: MRPS34 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPS34 were set to 41506652 Phenotypes for gene: MRPS34 were set to Cerebellar ataxia, distal motor neuropathy; pyramidal syndrome; leukoencephalopathy on brain MRI; Treatment with oral folinic acid Review for gene: MRPS34 was set to AMBER Added comment: One case associated with neuropathy. A likely cause of neuropathy as multiple other cerebral folate gene variants also causing neuropathy as part of extended phenotype. Certainly not green at this stage but no good evidence it isn't pathogenic so should not be downgraded to red Sources: Other |
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| Hereditary neuropathy or pain disorder v8.33 | MRPS23 |
Alexander Rossor gene: MRPS23 was added gene: MRPS23 was added to Hereditary neuropathy or pain disorder. Sources: Other Mode of inheritance for gene: MRPS23 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPS23 were set to 41506652 Phenotypes for gene: MRPS23 were set to Cerebellar ataxia, distal motor neuropathy; pyramidal syndrome; leukoencephalopathy on brain MRI; Treatment with oral folinic acid Review for gene: MRPS23 was set to AMBER Added comment: One case associated with neuropathy. A likely cause of neuropathy as multiple other cerebral folate gene variants also causing neuropathy as part of extended phenotype. Certainly not green at this stage but no good evidence it isn't pathogenic so should not be downgraded to red Sources: Other |
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| Hereditary neuropathy or pain disorder v8.33 | MRPS22 |
Alexander Rossor gene: MRPS22 was added gene: MRPS22 was added to Hereditary neuropathy or pain disorder. Sources: Other Mode of inheritance for gene: MRPS22 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPS22 were set to 41506652 Phenotypes for gene: MRPS22 were set to Cerebellar ataxia, distal motor neuropathy; pyramidal syndrome; leukoencephalopathy on brain MRI; Treatment with oral folinic acid Review for gene: MRPS22 was set to AMBER Added comment: Once case associated with neuropathy. A likely cause of neuropathy as multiple other cerebral folate gene variants also causing neuropathy as part of extended phenotype. Certainly not green at this stage but no good evidence it isn't pathogenic so should not be downgraded to red Sources: Other |
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| Hereditary neuropathy or pain disorder v8.33 | FOLR1 |
Alexander Rossor gene: FOLR1 was added gene: FOLR1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FOLR1 were set to 27743887 Phenotypes for gene: FOLR1 were set to Developmental regression; epilepsy; leukodystrophy; cerebellar atrophy; axonal neuropathy Review for gene: FOLR1 was set to AMBER Added comment: Once case associated with neuropathy. A likely cause of neuropathy as multiple other cerebral folate gene variants also causing neuropathy as part of extended phenotype. Certainly not green at this stage but no good evidence it isn't pathogenic so should not be downgraded to red Sources: Expert list |
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| Paediatric or syndromic cardiomyopathy v8.14 | DSG2 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least three unrelated cases reported with childhood/ juvenile onset cardiomyopathy. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal ' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.14 | DSG2 | Achchuthan Shanmugasundram Mode of inheritance for gene: DSG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.13 | DSG2 | Achchuthan Shanmugasundram Phenotypes for gene: DSG2 were changed from Cardiomyopathy, dilated, 1BB,; Arrhythmogenic right ventricular dysplasia 10 to Arrhythmogenic right ventricular dysplasia 10, OMIM:610193; arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Cardiomyopathy, dilated, 1BB, OMIM:612877; dilated cardiomyopathy 1BB, MONDO:0013030 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.12 | DSG2 | Achchuthan Shanmugasundram Publications for gene: DSG2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.11 | DSG2 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: DSG2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.11 | DSG2 | Achchuthan Shanmugasundram reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31645976, 33949662, 37288269, 39706847; Phenotypes: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434, Cardiomyopathy, dilated, 1BB, OMIM:612877, dilated cardiomyopathy 1BB, MONDO:0013030; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.11 | DSG2 |
Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in DSG2 gene with arrhythmogenic right ventricular cardiomyopathy. There are also two biallelic cases reported with dilated cardiomyopathy. The GMS Cardiology Specialist Group decided that all green genes that are present on the Arrhythmogenic right ventricular cardiomyopathy panel should also be green on this panel due to possible phenotypic overlap. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. |
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| Dilated and arrhythmogenic cardiomyopathy v4.11 | DSG2 | Achchuthan Shanmugasundram Mode of inheritance for gene: DSG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.10 | DSG2 |
Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: DSG2. Tag Q3_26_MOI tag was added to gene: DSG2. |
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| Arrhythmogenic right ventricular cardiomyopathy v3.21 | DSG2 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: DSG2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.10 | DSG2 | Achchuthan Shanmugasundram Publications for gene: DSG2 were set to 23500315; 27532257 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.9 | DSG2 | Achchuthan Shanmugasundram Phenotypes for gene: DSG2 were changed from Arrhythmogenic right ventricular dysplasia 10; Arrhythmogenic right ventricular dysplasia 10 (610193); Cardiomyopathy, dilated, 1BB (612877) to Arrhythmogenic right ventricular dysplasia 10, OMIM:610193; arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Cardiomyopathy, dilated, 1BB, OMIM:612877; dilated cardiomyopathy 1BB, MONDO:0013030 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.8 | DSG2 | Achchuthan Shanmugasundram edited their review of gene: DSG2: Changed publications to: 16773573, 18678517, 28818065, 30454721, 31645976, 33949662, 37288269, 39706847 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.8 | DSG2 |
Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877). Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877). Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis. Below are reported cases with biallelic variants and dilated cardiomyopathy: PMID:18678517 (2008) reported a single index case with dilated cardiomyopathy and carried a homozygous DSG2 p.Val55Met/ p.Val56Met variant, with an affected father and an asymptomatic mother both identified as heterozygous carriers. A broader cohort screen of 538 idiopathic DCM patients found 13 additional heterozygous carriers versus 3 in 617 controls. PMID:33949662 (2021) reported the identification of a homozygous p.Arg119Ter variant in a patient with juvenile-onset severe biventricular heart failure, for which iPSC-cardiomyocyte modeling showed disrupted desmosome deposition and abnormal intercalated discs. |
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| Dilated and arrhythmogenic cardiomyopathy v4.8 | DSG2 |
Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen. Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but associated with dilated cardiomyopathy in OMIM (MIM #612877). Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis. |
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| Dilated and arrhythmogenic cardiomyopathy v4.8 | DSG2 | Achchuthan Shanmugasundram edited their review of gene: DSG2: Changed phenotypes to: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434, Cardiomyopathy, dilated, 1BB, OMIM:612877, dilated cardiomyopathy 1BB, MONDO:0013030 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.8 | DSG2 | Achchuthan Shanmugasundram reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16773573, 28818065, 30454721, 31645976, 37288269, 39706847; Phenotypes: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.28 | AIMP2 |
Ida Ertmanska changed review comment from: Additional cases: PMID: 38374194 Abolhassani et al., 2024 Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT). PMID: 35140751 Mazaheri et al., 2022 Iranian proband - 7-month-old infant with a progressive neurological disorder characterized by lack of development, weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD. PMID: 35568357 Masih et al., 2022 Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17. PMID: 26795593 Helbig et al., 2016 Proband with Epileptic encephalopathy. Compound het for AIMP2 c.575-2A>G and c.72_73del (p.Met24IlefsTer25). Patient also has alteration in LRFN2 (not associated with disease in OMIM). This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2025). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).; to: Additional cases: PMID: 38374194 Abolhassani et al., 2024 Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT). PMID: 35140751 Mazaheri et al., 2022 Iranian proband - 7-month-old infant with a progressive neurological disorder characterized by lack of development, weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD. PMID: 35568357 Masih et al., 2022 Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17. PMID: 26795593 Helbig et al., 2016 Proband with Epileptic encephalopathy. Compound het for AIMP2 c.575-2A>G and c.72_73del (p.Met24IlefsTer25). Patient also has alteration in LRFN2 (not associated with disease in OMIM). This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2026). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025). |
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| Arrhythmogenic right ventricular cardiomyopathy v3.21 | DSG2 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in DSG2 gene with arrhythmogenic right ventricular cardiomyopathy. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arrhythmogenic right ventricular cardiomyopathy v3.21 | DSG2 | Achchuthan Shanmugasundram Mode of inheritance for gene: DSG2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arrhythmogenic right ventricular cardiomyopathy v3.20 | DSG2 |
Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen. Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel) and all these records were last accessed on 04 September 2026. However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen. Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis. |
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| Arrhythmogenic right ventricular cardiomyopathy v3.20 | DSG2 | Achchuthan Shanmugasundram Phenotypes for gene: DSG2 were changed from Cardiomyopathy, dilated, 1BB (612877); Arrhythmogenic right ventricular dysplasia 10 ; Arrhythmogenic right ventricular dysplasia 10 (610193) to Arrhythmogenic right ventricular dysplasia 10, OMIM:610193; arrhythmogenic right ventricular dysplasia 10, MONDO:0012434 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arrhythmogenic right ventricular cardiomyopathy v3.19 | DSG2 | Achchuthan Shanmugasundram Publications for gene: DSG2 were set to 27532257; 23500315; 29567486 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arrhythmogenic right ventricular cardiomyopathy v3.18 | DSG2 | Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: DSG2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arrhythmogenic right ventricular cardiomyopathy v3.18 | DSG2 |
Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen. Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen. Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:30454721 (2019) reported screening of a cohort of 118 Chinese ARVC probands and found DSG2 p.Phe531Cys as an East Asian founder variant in 12 patients, causing full-penetrance ARVC when homozygous while heterozygous carriers remained largely unaffected, supporting an autosomal recessive inheritance pattern. The variant is extremely rare in reference populations (gnomAD MAF 5.78×10⁻⁵), highly conserved, and located in DSG2's extracellular anchor domain. PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis. |
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| Arrhythmogenic right ventricular cardiomyopathy v3.18 | DSG2 | Achchuthan Shanmugasundram edited their review of gene: DSG2: Changed publications to: 16773573, 28818065, 30454721, 31645976, 37288269, 39706847 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arrhythmogenic right ventricular cardiomyopathy v3.18 | DSG2 |
Achchuthan Shanmugasundram changed review comment from: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen. Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis.; to: Monoallelic variants in this gene has been associated with arrhythmogenic right ventricular cardiomyopathy in OMIM (MIM #610193), ClinGen (with 'Definitive' rating by Arrhythmogenic Right Ventricular Cardiomyopathy GCEP) and Gene2Phenotype (with definitive rating on the Cardiac panel). However, biallelic variants are associated with DSG2-related arrhythmogenic right ventricular cardiomyopathy only in Gene2Phenotype (with definitive rating on the Cardiac panel), but not in OMIM or ClinGen. Below are reported cases with biallelic variants and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC): PMID:16773573 (2006) reported a compound heterozygous case (Family B, proband B.II-1): a 42-year-old with ARVC carrying c.143G>A (p.Arg48His) and c.915G>A (p.Trp305Ter) in trans. The mother carried only the p.Trp305Ter allele and was clinically unaffected, while the p.Arg48His allele was of paternal origin (father deceased before testing, so full segregation could not be confirmed). PMID:28818065 (2017) reported two unrelated Finnish families with a total of five homozygous carriers of c.1003A>G (p.Thr335Ala) all met ARVC diagnostic criteria, while nine heterozygous relatives across both pedigrees were clinically unaffected. This variant is common in gnomAD, with allele count of 1121. However, no homozygotes were present and ClinVar currently lists its overall clssifiction as "Conflicting". PMID:31645976 (2019) reported two East Asian ARVC families: Family A's proband carried compound heterozygous c.146G>A (p.Arg49His, paternally inherited) plus c.1592T>G (p.Phe531Cys), while Family B's proband was homozygous for p.Phe531Cys alone. PMID:37288269 (2023) reported a single paediatric proband (8 years old) presented with arrhythmogenic cardiomyopathy initially misdiagnosed as myocarditis, driven by homozygous c.1592T>G (p.Phe531Cys), identified via whole-exome sequencing. PMID:39706847 (2024) reported four unrelated Japanese patients with heterozygous p.Arg119Ter, of which one (Pt-1, a 19-year-old woman with ARVC) was compound heterozygous, carrying p.Arg119Ter together with p.Arg292Cys; her mother, a heterozygous p.Arg119Ter carrier alone, had an enlarged heart on chest X-ray but no formal ARVC diagnosis. |
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| Arrhythmogenic right ventricular cardiomyopathy v3.18 | DSG2 | Achchuthan Shanmugasundram reviewed gene: DSG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16773573, 28818065, 31645976, 37288269, 39706847; Phenotypes: Arrhythmogenic right ventricular dysplasia 10, OMIM:610193, arrhythmogenic right ventricular dysplasia 10, MONDO:0012434; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.8 | CRYAB | Achchuthan Shanmugasundram Classified gene: CRYAB as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.8 | CRYAB | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with isolated dilated cardiomyopathy (DCM). However, the variant was not specified for one of the cases. Hence, the gene should be rated amber with 'watchlist' tagged added for future review with new evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.8 | CRYAB | Achchuthan Shanmugasundram Gene: cryab has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.7 | CRYAB | Achchuthan Shanmugasundram Phenotypes for gene: CRYAB were changed from Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810 to Cardiomyopathy, dilated, 1II, OMIM:615184; dilated cardiomyopathy 1II, MONDO:0014073 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.6 | CRYAB | Achchuthan Shanmugasundram Publications for gene: CRYAB were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.5 | CRYAB | Achchuthan Shanmugasundram Mode of inheritance for gene: CRYAB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.4 | CRYAB | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: CRYAB. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.4 | CRYAB | Achchuthan Shanmugasundram reviewed gene: CRYAB: Rating: AMBER; Mode of pathogenicity: None; Publications: 40046506, 41153379, 42170542; Phenotypes: Cardiomyopathy, dilated, 1II, OMIM:615184, dilated cardiomyopathy 1II, MONDO:0014073; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.11 | CRYAB | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are at least five unrelated families reported with syndromic or early onset crdiomyopathy, particulrly dilated cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are at least five unrelated families reported with syndromic or early onset crdiomyopathy, particularly dilated cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.11 | CRYAB | Achchuthan Shanmugasundram Classified gene: CRYAB as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.11 | CRYAB | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least five unrelated families reported with syndromic or early onset crdiomyopathy, particulrly dilated cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.11 | CRYAB | Achchuthan Shanmugasundram Gene: cryab has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.10 | CRYAB | Achchuthan Shanmugasundram Phenotypes for gene: CRYAB were changed from Cardiomyopathy, dilated, 1II, OMIM:615184; Myopathy, myofibrillar, 2, OMIM:608810 to Cardiomyopathy, dilated, 1II, OMIM:615184; dilated cardiomyopathy 1II, MONDO:0014073; Myopathy, myofibrillar, 2A, adult-onset, OMIM:608810; myofibrillar myopathy 2, MONDO:0012130 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.9 | CRYAB | Achchuthan Shanmugasundram Publications for gene: CRYAB were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.8 | CRYAB | Achchuthan Shanmugasundram Mode of inheritance for gene: CRYAB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.7 | CRYAB | Achchuthan Shanmugasundram Tag Q3_26_demote_amber tag was added to gene: CRYAB. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.7 | CRYAB | Achchuthan Shanmugasundram reviewed gene: CRYAB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27904835, 28493373, 32420686, 38212463, 42170542; Phenotypes: Cardiomyopathy, dilated, 1II, OMIM:615184, dilated cardiomyopathy 1II, MONDO:0014073, Myopathy, myofibrillar, 2A, adult-onset, OMIM:608810, myofibrillar myopathy 2, MONDO:0012130; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | PAX3 | Ida Ertmanska reviewed gene: PAX3: Rating: RED; Mode of pathogenicity: None; Publications: 7726174, 12949970, 26443304, 35607853, 41141997, 41159045; Phenotypes: Waardenburg syndrome, type 1, OMIM:193500, Waardenburg syndrome type 1, MONDO:0008670, Waardenburg syndrome, type 3, OMIM:148820, Waardenburg syndrome type 3, MONDO:0007862, Klein-Waardenburg syndrome; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.13 | CNP | Achchuthan Shanmugasundram Classified gene: CNP as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.13 | CNP | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated families and functional evidence including mouse model in support of the association of CNP with leukodystrophy. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.13 | CNP | Achchuthan Shanmugasundram Gene: cnp has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.12 | CNP |
Achchuthan Shanmugasundram Tag watchlist was removed from gene: CNP. Tag Q3_26_promote_green tag was added to gene: CNP. |
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| White matter disorders and cerebral calcification - childhood onset v8.12 | CNP | Achchuthan Shanmugasundram Phenotypes for gene: CNP were changed from ?Leukodystrophy, hypomyelinating, 20, OMIM:619071 to ?Leukodystrophy, hypomyelinating, 20, OMIM:619071; leukodystrophy, hypomyelinating, 20, MONDO:0033657 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.11 | CNP | Achchuthan Shanmugasundram Publications for gene: CNP were set to 32128616; 12590258 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.10 | CNP |
Achchuthan Shanmugasundram changed review comment from: PMID:32128616 (2020) reported a consanguineous Omani family with three affected siblings displaying a remarkably consistent phenotype of neuroregression with profound brain white matter loss. They were identified with a homozygous missense variant c.245C>T (p.Ser82Leu) in CNP gene, suggested to function as a null allele (immunoblot + F-actin defects in fibroblasts). PMID:40396300 (2025) reported a novel case of a child presenting with hypomyelinating leukodystrophy type 20, and identified with homozygous nonsense variant c.295G>T (p.Glu99Ter), supported by RT-qPCR showing reduced CNP mRNA. PMID:12590258 (2003) reported that deficiency of CNP in mice led to axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. This gene has been tentatively associated with hypomyelinating leukodystrophy in OMIM (MIM #619071), but not in Gene2Phenotype or ClinGen.; to: PMID:32128616 (2020) reported a consanguineous Omani family with three affected siblings displaying a remarkably consistent phenotype of neuroregression with profound brain white matter loss. They were identified with a homozygous missense variant c.245C>T (p.Ser82Leu) in CNP gene, suggested to function as a null allele (immunoblot + F-actin defects in fibroblasts). PMID:40396300 (2025) reported a novel case of a child presenting with hypomyelinating leukodystrophy type 20, and identified with homozygous nonsense variant c.295G>T (p.Glu99Ter), supported by RT-qPCR showing reduced CNP mRNA. PMID:12590258 (2003) reported that deficiency of CNP in mice led to axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. This gene has been tentatively associated with hypomyelinating leukodystrophy in OMIM (MIM #619071 - last accessed 03 September 2026), but not in Gene2Phenotype or ClinGen. |
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| White matter disorders and cerebral calcification - childhood onset v8.10 | CNP | Achchuthan Shanmugasundram reviewed gene: CNP: Rating: GREEN; Mode of pathogenicity: None; Publications: 12590258, 32128616, 40396300; Phenotypes: ?Leukodystrophy, hypomyelinating, 20, OMIM:619071, leukodystrophy, hypomyelinating, 20, MONDO:0033657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: POLR3K. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.35 | POLR3K | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: POLR3K. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.13 | POLR3K | Achchuthan Shanmugasundram Phenotypes for gene: POLR3K were changed from Leukodystrophy, hypomyelinating, 21, OMIM:619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310; leukodystrophy, hypomyelinating, 21, MONDO:0030263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.12 | POLR3K | Achchuthan Shanmugasundram Publications for gene: POLR3K were set to 30584594; 33659930 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.11 | POLR3K | Achchuthan Shanmugasundram reviewed gene: POLR3K: Rating: AMBER; Mode of pathogenicity: None; Publications: 30584594, 40225923; Phenotypes: Leukodystrophy, hypomyelinating, 21, OMIM:619310, leukodystrophy, hypomyelinating, 21, MONDO:0030263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.35 | POLR3K | Achchuthan Shanmugasundram Classified gene: POLR3K as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.35 | POLR3K | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases (counting the two cases with potential founder variant as one) reported with three different variants in POLR3K (two cases homozygous for the suggested founder missense variant and one case compound heterozygous for a different missense variant and a ~17.8 kb deletion). All patients had cerebellar atrophy and two of them had ataxia. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.35 | POLR3K | Achchuthan Shanmugasundram Gene: polr3k has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.34 | POLR3K | Achchuthan Shanmugasundram Tag watchlist was removed from gene: POLR3K. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.34 | POLR3K | Achchuthan Shanmugasundram Publications for gene: POLR3K were set to 30584594; 33659930 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.33 | POLR3K | Achchuthan Shanmugasundram Phenotypes for gene: POLR3K were changed from Leukodystrophy, hypomyelinating, 21, OMIM:619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310; leukodystrophy, hypomyelinating, 21, MONDO:0030263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.32 | POLR3K | Achchuthan Shanmugasundram reviewed gene: POLR3K: Rating: GREEN; Mode of pathogenicity: None; Publications: 30584594, 40225923; Phenotypes: Leukodystrophy, hypomyelinating, 21, OMIM:619310, leukodystrophy, hypomyelinating, 21, MONDO:0030263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K |
Achchuthan Shanmugasundram changed review comment from: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype (onset was in late childhood/ adolescence). This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053). |
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| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K |
Achchuthan Shanmugasundram changed review comment from: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp), with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053).; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053). |
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| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K | Achchuthan Shanmugasundram Tag watchlist was removed from gene: POLR3K. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K | Achchuthan Shanmugasundram Classified gene: POLR3K as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases (counting the two cases with potential founder variant as one) reported with three different variants in POLR3K (two cases homozygous for the suggested founder missense variant and one case compound heterozygous for a different missense variant and a ~17.8 kb deletion). There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.10 | POLR3K | Achchuthan Shanmugasundram Gene: polr3k has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.9 | POLR3K | Achchuthan Shanmugasundram Phenotypes for gene: POLR3K were changed from Leukodystrophy, hypomyelinating, 21, OMIM:619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310; leukodystrophy, hypomyelinating, 21, MONDO:0030263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.8 | POLR3K | Achchuthan Shanmugasundram Publications for gene: POLR3K were set to 30584594; 33659930 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.7 | POLR3K |
Achchuthan Shanmugasundram changed review comment from: PMID:40225923 (2024) reported a single female patient compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.; to: PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp), with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). In both cases, a diffuse hypomyelinating aspect of the white matter was observed on MRI excepted in the early first myelinated area of the brainstem, associated with atrophy of the corpus callosum and cerebellum. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control. PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype. This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant. This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053). |
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| White matter disorders and cerebral calcification - childhood onset v8.7 | POLR3K | Achchuthan Shanmugasundram edited their review of gene: POLR3K: Changed publications to: 30584594, 40225923 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.7 | POLR3K | Achchuthan Shanmugasundram reviewed gene: POLR3K: Rating: GREEN; Mode of pathogenicity: None; Publications: 40225923; Phenotypes: Leukodystrophy, hypomyelinating, 21, OMIM:619310, leukodystrophy, hypomyelinating, 21, MONDO:0030263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | NSMCE2 | Ida Ertmanska Classified gene: NSMCE2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | NSMCE2 | Ida Ertmanska Added comment: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including IUGR and oligohydramnios noted on prenatal scans. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.7 | NSMCE2 | Ida Ertmanska Gene: nsmce2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.6 | NSMCE2 |
Ida Ertmanska gene: NSMCE2 was added gene: NSMCE2 was added to Fetal anomalies. Sources: Literature Q3_26_promote_green tags were added to gene: NSMCE2. Mode of inheritance for gene: NSMCE2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NSMCE2 were set to 25105364; https://doi.org/10.1002/ajmg.a.70286 Phenotypes for gene: NSMCE2 were set to Seckel syndrome 10, OMIM:617253; Seckel syndrome, MONDO:0014991 Review for gene: NSMCE2 was set to GREEN Added comment: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before print Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans. His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD). PMID: 39184883 Tatiya, Kesri, and Ukey, 2024 14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made. PMID: 25105364 Payne et al., 2014 Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Both families are of European ancestry, and while not immediately related, they had shared common ancestral haplotypes. Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by re-expression of WT, but not SUMO-ligase–deficient NSMCE. Additional evidence (Decipher case): Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026). Sources: Literature |
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| Severe microcephaly v9.28 | NSMCE2 | Ida Ertmanska Phenotypes for gene: NSMCE2 were changed from Seckel syndrome 10, 617253; SCKL10 to Seckel syndrome 10, OMIM:617253; Seckel syndrome, MONDO:0014991 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.27 | NSMCE2 | Ida Ertmanska Classified gene: NSMCE2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.27 | NSMCE2 | Ida Ertmanska Added comment: Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.27 | NSMCE2 | Ida Ertmanska Gene: nsmce2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.26 | NSMCE2 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: NSMCE2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.26 | NSMCE2 |
Ida Ertmanska changed review comment from: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before publication Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans. His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD). PMID: 39184883 Tatiya, Kesri, and Ukey, 2024 14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made. PMID: 25105364 Payne et al., 2014 Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE. Additional evidence (Decipher case): Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).; to: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before print Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans. His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD). PMID: 39184883 Tatiya, Kesri, and Ukey, 2024 14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made. PMID: 25105364 Payne et al., 2014 Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE. Additional evidence (Decipher case): Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026). |
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| Severe microcephaly v9.26 | NSMCE2 |
Ida Ertmanska changed review comment from: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before publication Study described an 11-year-old male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).; to: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before publication Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans. His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD). PMID: 39184883 Tatiya, Kesri, and Ukey, 2024 14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made. PMID: 25105364 Payne et al., 2014 Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE. Additional evidence (Decipher case): Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026). |
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| Severe microcephaly v9.26 | NSMCE2 |
Ida Ertmanska changed review comment from: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 Study described an 11-year-old male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).; to: https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before publication Study described an 11-year-old male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026). |
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| Severe microcephaly v9.26 | NSMCE2 | Ida Ertmanska reviewed gene: NSMCE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25105364, https://doi.org/10.1002/ajmg.a.70286; Phenotypes: Seckel syndrome 10, OMIM:617253, Seckel syndrome, MONDO:0014991; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.25 | CACNA1C | Ida Ertmanska commented on gene: CACNA1C: Comment on list classification: There are several individuals reported in literature with monoallelic CACNA1C variants and Short QT Syndrome (SQTS), or Brugada syndrome with SQTS. However, this association has been classified as Disputed in ClinGen. Some allele frequencies are too high in population databases, there is little functional evidence supporting the variant pathogenicity, and most variants are ranked as VUS according to ACMG criteria. There is no robust evidence linking SQTS to CACNA1C variants. Hence this gene should be demoted at the next GMS update. An expert-review tag was added as this is a proposed demotion of a Green gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.25 | CACNA1C | Ida Ertmanska edited their review of gene: CACNA1C: Changed phenotypes to: Brugada syndrome 3, OMIM:611875, Timothy syndrome, OMIM:601005, Long QT syndrome 8, OMIM:618447 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.25 | CACNA1C | Ida Ertmanska Publications for gene: CACNA1C were set to 24291113; 16301704; 30027834; 30279520; 17224476; 28427417; 28490369; 29759541; 29697308 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.24 | CACNA1C | Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CACNA1C. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.24 | CACNA1C | Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: CACNA1C. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.24 | CACNA1C | Ida Ertmanska edited their review of gene: CACNA1C: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.24 | CACNA1C |
Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary: PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact. PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype PMID: 30571592 El-Battrawy et al., 2018 Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen. PMID: 39503779 Martínez-Barrios et al., 2024 - lit review "Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CACNA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary: PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact. PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype CACNA1C association with AD Brugada syndrome is also Disputed in ClinGen as of 2025: "Many reported variants in CACNA1C are too common in population databases, and functional studies have shown that both common and rare variants can produce similar effects [PMID: 17224476, 20817017]." PMID: 30571592 El-Battrawy et al., 2018 Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen. PMID: 34999275 Novelli et al., 2022 563 BrS probands underwent CACNA1C sequencing - identified 11 different rare variants in 9 patients. Most of these were classified as VUS according to ACMG criteria. "CACNA1C is an infrequent but definitive cause of BrS typically associated with short QT." PMID: 39503779 Martínez-Barrios et al., 2024 - lit review "Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations." |
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| Short QT syndrome v3.24 | CACNA1C |
Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary: PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact. PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype PMID: 30571592 El-Battrawy et al., 2018 Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. PMID: 39503779 Martínez-Barrios et al., 2024 - lit review "Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary: PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact. PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype PMID: 30571592 El-Battrawy et al., 2018 Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen. PMID: 39503779 Martínez-Barrios et al., 2024 - lit review "Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations." |
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| Short QT syndrome v3.24 | CACNA1C |
Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary: PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact. PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype PMID: 30571592 El-Battrawy et al., 2018 Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. PMID: 39503779 Martínez-Barrios et al., 2024 - lit review "Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary: PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact. PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype PMID: 30571592 El-Battrawy et al., 2018 Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. PMID: 39503779 Martínez-Barrios et al., 2024 - lit review "Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations." |
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| Short QT syndrome v3.24 | CACNA1C |
Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary: PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact. PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary: PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact. PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype PMID: 30571592 El-Battrawy et al., 2018 Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. PMID: 39503779 Martínez-Barrios et al., 2024 - lit review "Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations." |
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| Short QT syndrome v3.24 | CACNA1C | Ida Ertmanska reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: 17224476, 20817017, 24291113, 28427417; Phenotypes: Brugada syndrome 3, OMIM:611875, Timothy syndrome, OMIM:601005, Long QT syndrome 8, OMIM:618447, Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, OMIM:620029; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.14 | RYR3 |
Ida Ertmanska gene: RYR3 was added gene: RYR3 was added to Paediatric disorders - additional genes. Sources: Literature Mode of inheritance for gene: RYR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RYR3 were set to 39762984; 41022857 Phenotypes for gene: RYR3 were set to congenital heart disease, MONDO:0005453 Review for gene: RYR3 was set to RED Added comment: PMID: 39762984 Kim et al., 2025 Trio WGS study of 18 probands with congenital anomalies. P4 = het de novo c.12295G > T (p.Glu4099Ter) variant in RYR3; patient features: duodenal atresia, cardiovascular abnormalities, and vesicoureteral reflux. Variant not in gnomAD v4.1.1. Zebrafish ryr3 knockout showed enlarged atria and ventricle compared to controls at 3dpf. PMID: 41022857 Jeong & Bulyk, 2025 Study investigated congenital heart defect (CHD) and orofacial cleft (OFC) parent-offspring trio cohorts (n = 3835 and 1844, respectively). 4 de novo missense (L110I, S2130L, Y2743C, F2957L) variants identified in a CHD cohort. Y2743C has a homozygote & MAF=0.0002760 in gnomAD (higher than expected for AD disease). Sources: Literature |
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| Early onset or syndromic epilepsy v9.76 | RYR3 | Ida Ertmanska commented on gene: RYR3: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3: 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, 3 with syndromic contractures, and some studies report an association with congenital heart disease. There are at least 15 individuals, primarily of Chinese origin, with RYR3 variants and a developmental and epileptic encephalopathy. 4 individuals harboured heterozygous de novo variants, while 11/15 harboured biallelic RYR3 variants (primarily missense and splice). Additional variable features included developmental delay, hypotonia, dystonia, motor dyspraxia. Based on the confounding literature, a ClinGen Limited classification, limited functional evidence, and common variants being reported as causal, this gene should remain Amber, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452). The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. RYR3 is only associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2024 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. Normal muscle strength and tone in all extremities, normal head MRI. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452). The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. RYR3 is only associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026). |
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| Congenital myopathy v7.81 | RYR3 | Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a proposed demotion of a Green gene, an expert-review tag was added.; to: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, sometimes with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a proposed demotion of a Green gene, an expert-review tag was added. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.81 | RYR3 | Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a demotion of a Green gene, an expert-review tag was added.; to: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a proposed demotion of a Green gene, an expert-review tag was added. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.81 | RYR3 | Ida Ertmanska Publications for gene: RYR3 were set to 29498452 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: RYR3. Tag Q3_26_demote_red tag was added to gene: RYR3. |
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| Congenital myopathy v7.80 | RYR3 | Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges.; to: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. As this is a demotion of a Green gene, an expert-review tag was added. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.80 | RYR3 | Ida Ertmanska commented on gene: RYR3: Comment on list classification: There are numerous patients reported in literature with both mono- and bi-allelic variants in RYR3. However, only 1 individual (PMID 29498452) was reported with a childhood-onset myopathy, confirmed by biopsy and EMG. Other patients presented with developmental and epileptic encephalopathy, with additional features of hypotonia, dystonia, motor dyspraxia. RYR3 has also been implicated in congenital heart disease. Based on the confounding literature, a ClinGen Disputed classification, and no functional evidence to support this association, this gene should be demoted to Red, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy. WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Partial phenotype overlap: some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).; to: PMID 29498452 Nilipour et al., 2018 Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy. WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) - 6mo female with arthrogryposis multiplex congenita, hypotonia, facial dysmorphism. Comp het variants in MYO18B also detected. PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A - female with bilateral clubfoot, finger contractures, GDD, enteropathy. She had repeated episodes resembling seizures around age 2 yrs - these resolved without treatment. No signs of muscle disease. CGH array detected a 144kb microdeletion in 6q22.31 of unknown significance. BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) - 15yo female with high arched palate, contractures, ulnar deviation, scoliosis. Parents are consanguineous. Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Partial phenotype overlap: some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026). |
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| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy. WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).; to: PMID 29498452 Nilipour et al., 2018 Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy. WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Partial phenotype overlap: some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026). |
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| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026).; to: PMID 29498452 Nilipour et al., 2018 Reported a 22yo female individual with nemaline myopathy and harboring two unique RYR3 missense variants. She presented at 5yo with muscle weakness. At 22yo she had facial weakness, mild scapular winging, proximal limb weakness, high arched palate, and micrognathia. Muscle strength was 4/5 and 5/5 in the limbs. EMG showed myopathic potentials. Muscle biopsy showed features consistent with nemaline myopathy. WES identified comp het variants in RYR3: c.6208A>G, p.Met2070Val (MAF = 0.0007467 in gnomAD v4, no hmz) & c.8939G>T, p.Arg2980Leu (MAF=0.001644 in gnomAD v4, no hmz). Variants confirmed in trans, het parents unaffected. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026). |
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| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). RYR3 is associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026). |
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| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452). The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452). The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. RYR3 is only associated with AR Congenital myopathy 20, OMIM:620310 in OMIM (accessed 3rd Sept 2026). |
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| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. There are also 3 individuals reported with biallelic RYR3 variants and arthrogryposis (PMID: 31230720), and one with recessive congenital myopathy (PMID: 29498452). The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. |
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| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. A couple of the reported variants are fairly common and have homozygotes reported in gnomAD v4. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. |
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| Neurodegenerative disorders, adult onset v9.12 | VPS13C | Achchuthan Shanmugasundram Classified gene: VPS13C as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.12 | VPS13C | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least 10 unrelated patients available in support of the association of this gene with early-onset Parkinson's disease. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.12 | VPS13C | Achchuthan Shanmugasundram Gene: vps13c has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.11 | VPS13C | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: VPS13C. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.11 | VPS13C | Achchuthan Shanmugasundram reviewed gene: VPS13C: Rating: GREEN; Mode of pathogenicity: None; Publications: 26942284, 28862745, 30452786, 33579389, 34875562; Phenotypes: Parkinson disease 23, early onset, OMIM:616840, autosomal recessive early-onset Parkinson disease 23, MONDO:0014796; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., https://doi.org/10.1016/j.gendis.2026.102341). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., Xu et al., 2026). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). |
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| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., https://doi.org/10.1016/j.gendis.2026.102341). The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., https://doi.org/10.1016/j.gendis.2026.102341). Other studies reported RYR3 varians in patients with congenital heart disease: PMID: 39762984; PMID: 41022857. The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). |
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| Malformations of cortical development v8.11 | TMEM161B | Alexandra Njegic reviewed gene: TMEM161B: Rating: AMBER; Mode of pathogenicity: None; Publications: 36669111, 38593811, 37486637; Phenotypes: Polymicrogyria; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | RYR3 | Ida Ertmanska edited their review of gene: RYR3: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). Some patients showed hypotonia, dystonia, motor dyspraxia (e.g., https://doi.org/10.1016/j.gendis.2026.102341). The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). |
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| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, dystonia, gross motor dyspraxia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. |
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| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651;29667327;39220738;39840699, and https://doi.org/10.1016/j.gendis.2026.102341). The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651; 29667327; 39220738; 39840699, and https://doi.org/10.1016/j.gendis.2026.102341). The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). |
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| Congenital myopathy v7.80 | RYR3 |
Ida Ertmanska changed review comment from: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel).; to: PMID 29498452 Nilipour et al., 2018 Reported an affected individual with nemaline myopathy and harboring two unique RYR3 missense variants. PMID: 31230720 Pehlivan et al., 2019 Reported 3 unrelated individuals with biallelic RYR3 variants and arthrogryposis. BAB7845 - homozygous for RYR3: c.2486G>A (p.Arg829His) PAED187 - comp het for RYR3 c.2000A>G (p.Asp667Gly) & c.11164+1G>A BAB8988 - homozygous for RYR3: c.8939G>T (p.Arg2980Leu) Multiple other patients have been reported with mono- and bi-allelic RYR3 variants and developmental and epileptic encephalopathy (PMIDs:25262651;29667327;39220738;39840699, and https://doi.org/10.1016/j.gendis.2026.102341). The association between RYR3 and recessive congenital myopathy has been classified as Disputed in ClinGen in Oct 2025 (Congenital Myopathies Expert Panel). |
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| Early onset or syndromic epilepsy v9.76 | RYR3 | Ida Ertmanska edited their review of gene: RYR3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | RYR3 | Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 29667327, 39220738, 39840699, https://doi.org/10.1016/j.gendis.2026.102341 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 29667327 Peng et al., 2018 Study of Chinese patients with West syndrome (early infantile epileptic encephalopathy). Seq method: WES. 2 patients from family WS56 harboured biallelic RYR3 variants: c.A3716G, p.Lys1239Arg and c.C4046T, p.Thr1349Ile. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. |
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| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). Authors highlight that the mode of inheritance is RECESSIVE. PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. |
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| Early onset or syndromic epilepsy v9.76 | RYR3 | Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 39220738, 39840699, https://doi.org/10.1016/j.gendis.2026.102341 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: https://doi.org/10.1016/j.gendis.2026.102341 Xu et al., 2026 Study identified 5 individuals harboring compound heterozygous RYR3 variants, all presenting with early-onset epileptic spasms, hypsarrhythmia, and severe developmental delay. 4/5 patients developed drug-resistant epilepsy in the first year of life. Identified in a cohort of 420 patients with infantile epileptic spasm syndrome. Seq methid: Trio WES. FUNCTIONAL: The study established patient-derived induced pluripotent stem cells (iPSCs) from Proband 2 and differentiated them into cortical neurons. RYR3 H2626R/A3636G variants did not impair neural progenitor migration but caused significant neuronal developmental abnormalities, such as delayed maturation, shortened axons, and reduced branching - compared to control iPSCs from the patient’s mother (RYR3A3636G/+) and from an unrelated healthy individual (RYR3+/+). PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. |
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| Malformations of cortical development v8.11 | TMEM161B |
Alexandra Njegic gene: TMEM161B was added gene: TMEM161B was added to Malformations of cortical development. Sources: Literature Mode of inheritance for gene: TMEM161B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM161B were set to 36669111; 38593811; 37486637 Phenotypes for gene: TMEM161B were set to pol Penetrance for gene: TMEM161B were set to unknown |
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| Early onset or syndromic epilepsy v9.76 | RYR3 | Ida Ertmanska edited their review of gene: RYR3: Changed publications to: 25262651, 39220738, 39840699 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | RYR3 |
Ida Ertmanska changed review comment from: PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored.; to: PMID: 39840699 Tian et al., 2025 Study of 410 Han Chinese patients with partial (non-lesional) epilepsy without acquired causes. Seq method: Trio WES. RYR3 variants were identified in 7 unrelated patients with idiopathic epilepsy: 1 patient with a de novo het variant c.12947A>G, p.Glu4316Gly, and 6 individuals with comp het RYR3 variants - all unique missense. In biallelic cases, parents were confirmed het and asymptomatic. PMID: 39220738 Li et al., 2025 Report of a 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. WES identified a het RYR3 variant: c.10943C > T, p.T3648M. PMID: 25262651 EuroEPINOMICS-RES Consortium article, 2014 Reported 2 individuals with epilepsy and 2 unique de novo variants in RYR3: c.9603_9605del (p.Ile3203del) and .14104G>A (p.Asp4702Asn), respectively. The association between RYR3 and AD genetic developmental and epileptic encephalopathy has been classified as Limited in ClinGen (Oct 2023, Epilepsy Expert Panel) - only PMID: 25262651 was scored. |
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| Early onset or syndromic epilepsy v9.76 | RYR3 | Ida Ertmanska reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 39220738, 39840699; Phenotypes: developmental and epileptic encephalopathy, MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.80 | RYR3 | Ida Ertmanska reviewed gene: RYR3: Rating: RED; Mode of pathogenicity: None; Publications: 29498452, 31230720; Phenotypes: Congenital myopathy 20, OMIM:620310, congenital myopathy 20, MONDO:0957215; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.33 | EGR2 | Achchuthan Shanmugasundram Phenotypes for gene: EGR2 were changed from Charcot-Marie-Tooth disease, type 1D, MIM:607678; Dejerine-Sottas disease, MIM:145900; Hypomyelinating neuropathy, congenital, 1, MIM:605253 to Charcot-Marie-Tooth disease, type 1D, OMIM:607678; Dejerine-Sottas disease, OMIM:145900; Hypomyelinating neuropathy, congenital, 1, OMIM:605253 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.24 | CACNA1C | Ida Ertmanska Tag disputed tag was added to gene: CACNA1C. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.32 | HSPA9 | Ida Ertmanska Phenotypes for gene: HSPA9 were changed from Even-plus syndrome, OMIM:616854 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194; Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.25 | HSPA9 | Ida Ertmanska Phenotypes for gene: HSPA9 were changed from Even-plus syndrome, OMIM:616854; Anemia, sideroblastic, 4, OMIM:182170 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194; Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.31 | HSPA9 | Ida Ertmanska Publications for gene: HSPA9 were set to 26598328; 32869452; 35779070; 36052765 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.24 | HSPA9 | Ida Ertmanska Publications for gene: HSPA9 were set to 26491070; 26598328; 32869452; 35779070; 36052765 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.23 | HSPA9 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.30 | HSPA9 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.23 | HSPA9 | Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: As reviewed previously, there are more than 3 unrelated cases are reported with biallelic HSPA9 variants and EVEN-PLUS syndrome. There are also several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants and CSA (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Both EVEN-PLUS syndrome and Sideroblastic anemia stem from mitochondrial dysfunction. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.30 | HSPA9 | Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: As reviewed previously, there are more than 3 unrelated cases are reported with biallelic HSPA9 variants and EVEN-PLUS syndrome. There are also several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants and CSA (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Both EVEN-PLUS syndrome and Sideroblastic anemia stem from mitochondrial dysfunction. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.30 | HSPA9 | Ida Ertmanska reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212; Phenotypes: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194, Even-plus syndrome, OMIM:616854, even-plus syndrome, MONDO:0014801; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.23 | HSPA9 | Ida Ertmanska reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212; Phenotypes: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194, Even-plus syndrome, OMIM:616854, even-plus syndrome, MONDO:0014801; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.25 | HSPA9 | Ida Ertmanska Phenotypes for gene: HSPA9 were changed from Even-plus syndrome, OMIM:616854; Anemia, sideroblastic, 4, OMIM:182170 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194; Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.24 | HSPA9 | Ida Ertmanska Publications for gene: HSPA9 were set to 26491070; 26598328; 32869452; 35779070; 36052765 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.23 | HSPA9 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.23 | HSPA9 | Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: As reviewed previously, there are more than 3 unrelated cases are reported with biallelic HSPA9 variants and EVEN-PLUS syndrome. There are also several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants and CSA (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Both EVEN-PLUS syndrome and Sideroblastic anemia stem from mitochondrial dysfunction. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.23 | HSPA9 | Ida Ertmanska edited their review of gene: HSPA9: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska edited their review of gene: HSPA9: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska edited their review of gene: HSPA9: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.23 | HSPA9 |
Ida Ertmanska edited their review of gene: HSPA9: Added comment: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (pC487Sfs*3 & p.E577K in Family K; p.V296* & ?p.203_204ins3 in family L). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population. 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; Changed publications to: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212; Changed phenotypes to: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194, Even-plus syndrome, OMIM:616854, even-plus syndrome, MONDO:0014801; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal |
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| Rare anaemia v4.10 | HSPA9 | Ida Ertmanska Phenotypes for gene: HSPA9 were changed from sideroblastic anaemia; 182170 Sideroblastic anaemia 4; 182170 sideroblastic anaemia type 4; Sideroblastic anaemia type 4, 182170 to Anemia, sideroblastic, 4, OMIM:182170; sideroblastic anemia, MONDO:0015194 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.9 | HSPA9 | Ida Ertmanska Publications for gene: HSPA9 were set to 26491070 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 25550197, 26491070, 30401706, 33398880, 36094340, 38360212 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: HSPA9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation in HSPA9 is not sufficient to cause disease, these may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. ; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a homozygous rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update.; to: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a het/hom rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT in a homozygous state. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. While a single heterozygous mutation is not sufficient to cause disease, the high impact variants in HSPA9 may warrant further investigation of the haplotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska commented on gene: HSPA9: Comment on mode of inheritance: There are at several individuals reported in literature with HSPA9 variants and sideroblastic anemia (syndromic or non-syndromic). Most cases harboured a rare null or severe missense variant, as well as a homozygous rs10117T, (p.Leu645=) common variant, which has been shown to reduce HSPA9 protein expression to 80% of WT. Hence, a pseudodominant mode of inheritance was assigned to these pedigrees. There are also 2 recessive cases reported with rare biallelic HSPA9 variants (Families K & L in PMID: 26491070). Hence, the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population. 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (pC487Sfs*3 & p.E577K in Family K; p.V296* & ?p.203_204ins3 in family L). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population. 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). This variant has MAF = 0.8085 in East Asian population. 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 30401706 Ducamp & Fleming, 2018 review "a small minority of patients have the more prevalent, ancestral rs10117C allele in trans of a null or severe missense variant, suggesting the possibility that the rs10117T variant is in linkage disequilibrium with the “true” causative variant" PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a homozygous SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. FUNCTIONAL: Individuals homozygous for the rs10117T/T variant express approximately half as much HSPA9 mRNA and four-fifths as much HSPA9 protein as those who are homozygous for the rs10117C/C variant (qRT-PCR). PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. Patient VA-39 - 9yo female, presented with pallor, weakness, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia, ring sideroblasts, and short stature (no dysmorphism). She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants: Patient VA-39 - 9yo female, presented with pallor, weakness, severe anaemia, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. Patient JK-42 - 45yo female, who presented with pallor, weakness, mild anemia recognized in middle age, and vision problems consistent with retinitis pigmentosa; harboured c.866A>C, p.Glu289Ala and the L645= in trans in HSPA9. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. Described as pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Skeletal dysplasia v10.8 | HSPA9 | Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 26598328, DOI:10.4172/1747-0862.1000350, 32869452, 35779070, 36094340, 36052765 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients. P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees. P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification. F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature; to: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients. P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees. P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification. F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature |
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| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 26491070, 33398880, 36094340, 38360212 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. Patient VA-39 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/B in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 36094340 Watanabe et al., 2023 Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. Patient VA-39 - 9yo female, presented with pallor, weakness, and short stature. She harboured HSPA9 c.1064T>C, p.Val355Ala and L645= variants in trans. HSPA9 mRNA expression was noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Skeletal dysplasia v10.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients. P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees. P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature; to: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients. P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees. P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification. F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature |
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| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. Patient VA-39 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska edited their review of gene: HSPA9: Changed publications to: 26491070, 33398880, 38360212 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. "A phenotype permutation test yielded P < .07, suggesting that rs10117T or a linked variant determines expression of the HSPA9 CSA phenotype". The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Rare anaemia v4.8 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in HSPA9.; to: PMID: 26491070 Schmitz-Abe et al., 2015 Family A - Dutch pedigree with mild congenital sideroblastic anemia, inherited in an apparently autosomal dominant manner. HSPA9 NM_004134.6, c.409_410del, p.I137*) variant was detected. Family B - American. HSPA9: c.1373_1378del, p.Ile458_Asn459del was detected in affected individuals. Sequencing 88 other genetically undefined CSA probands identified 9 additional individuals with at least 1 rare HSPA9 variant. In families K and L, the mutations were biallelic by segregation (combination of 1 null and 1 missense or splicing variant). In 'dominant' pedigrees, the minor (T) sequence variant of the synonymous cSNP rs10117 (c.1933C>T, p.L645 = ) was present in trans of the mutant allele in 9 of 10 of the affected individuals. The rs10117 variant is classified as VUS/LB in ClinGen. SpliceAI prediction score is 0 (Benign). 2 unaffected family members reported with the same putative pathogenic HSPA9 variants as affected members - some incomplete penetrance. PMID: 33398880 Li et al., 2021 Case report of a Chinese woman with congenital sideroblastic anemia (CSA) - presented with pancytopenia and ring sideroblasts. She harboured a HSPA9 splice variant c.1515+1G>A (showed to cause exon skipping and NMD), and she was also homozygous for rs10117T. PMID: 38360212 Sharma et al., 2024 290 anemia cases were screened, with 2 cases harbouring HSPA9 variants. One of the two HSPA9 variant cases had severe anemia at a young age, whereas the other had mild anemia recognized in middle age but with vision problems consistent with retinitis pigmentosa. P1 - HSPA9 mRNA expression in patient with E289A and L645= variants in trans were noted to be 1000-fold lower than controls. P2 - harboured V355A and a polymorphism in trans in HSPA9. Pseudodominant inheritance. Functional: PMID: 25550197 Krysiak et al., 2016 Homozygous Hspa9 knockout in mice is embryonic lethal. Mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop myelodysplastic syndromes. |
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| Rare anaemia v4.8 | HSPA9 | Ida Ertmanska reviewed gene: HSPA9: Rating: GREEN; Mode of pathogenicity: None; Publications: 33398880, 38360212; Phenotypes: Anemia, sideroblastic, 4, OMIM:182170, sideroblastic anemia, MONDO:0015194; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | HSPA9 | Ida Ertmanska Classified gene: HSPA9 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.8 | HSPA9 | Ida Ertmanska Gene: hspa9 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.7 | HSPA9 | Ida Ertmanska Classified gene: HSPA9 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.7 | HSPA9 | Ida Ertmanska Added comment: Comment on list classification: Skeletal dysplasia is a major feature of EVEN-PLUS syndrome, caused by biallelic variants in HSPA9. There are at least 7 unrelated EVEN-PLUS families reported in literature, with characteristic skeletal features: hypoplastic nasal bones, dysplastic femoral heads, bifid distal femurs, dysplastic epiphyses, delayed ossification, and short stature. Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.7 | HSPA9 | Ida Ertmanska Gene: hspa9 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.6 | HSPA9 |
Ida Ertmanska changed review comment from: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature; to: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients. P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees. P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature |
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| Malformations of cortical development v8.11 | ATP1A2 | Eleanor Williams Phenotypes for gene: ATP1A2 were changed from Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, http://purl.obolibrary.org/obo/MONDO_0859204 to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MONDO:0859204 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.10 | ATP1A2 | Eleanor Williams Phenotypes for gene: ATP1A2 were changed from Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602 to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, http://purl.obolibrary.org/obo/MONDO_0859204 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.9 | ATP1A2 | Eleanor Williams Publications for gene: ATP1A2 were set to 30690204; 31608932 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.2 | FRYL |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is only evidence available from a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated amber. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of moderate and abiove should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P.; to: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is evidence available from only a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated green. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of 'moderate' and above should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P. |
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| DDG2P v8.2 | FRYL | Achchuthan Shanmugasundram Classified gene: FRYL as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.2 | FRYL |
Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julie Evans and detailed in my review below, there is only evidence available from a single publication to support the gene-disease association. The limitations listed including variability of phenotypes, large number of LoF variants in gnomAD 4.1.1 and the evidence from drosophila model not translating to humans due to humans having two paralogs suggest that this gene should not be rated amber. However, the DDG2P panel is not curated at Genomics England and is updated only to reflect the latest knowledge from the Gene2Phenotype resource (https://www.ebi.ac.uk/gene2phenotype/). Note that it was previously agreed with the G2P team and the NHSE that all genes with G2P classification of moderate and abiove should be rated green on this panel. Hence, the rating should stay green, pending updates from G2P. |
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| DDG2P v8.2 | FRYL | Achchuthan Shanmugasundram Gene: fryl has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.1 | FRYL |
Achchuthan Shanmugasundram changed review comment from: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. Overall, this represents a single-publication gene-disease claim with substantive unresolved population genetics and functional modelling concerns — further independent case series and reconciliation with gnomAD v4 constraint data are needed before upgrading to green.; to: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. |
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| DDG2P v8.1 | FRYL | Achchuthan Shanmugasundram edited their review of gene: FRYL: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.1 | FRYL |
Achchuthan Shanmugasundram edited their review of gene: FRYL: Added comment: PMID:38479391 (2024) reported 14 unrelated individuals with heterozygous FRYL variants (5 missense, 8 frameshift/stop-gain, 1 canonical splice) presenting with developmental delay/intellectual disability, dysmorphic features, and variable congenital anomalies across multiple systems. DD/ID was the only universal feature (14/14); all other phenotypes were variable and nonspecific, and 8/14 individuals harboured additional P/LP variants (in SF3B4, DHCR7, SLC6A19, SDHA) or VUSs in other genes that could partially confound phenotype attribution. Thirteen of 14 variants were confirmed de novo; the remaining variant (p.Ser2397Ile) was not confirmed de novo (duo testing could not exclude maternal inheritance), was present at low frequency in gnomAD, and showed no functional impact in Drosophila modelling — consistent with VUS rather than pathogenic classification. Of the 4/5 missense variants modelled using the fly fry ortholog, only 1 showed severe loss-of-function, 2 showed partial LoF, and 1 showed no effect, providing mixed functional support. Key concerns limiting confidence: (1) Half of the reported variants (7) are present in gnomAD v4.1.1. (2) gnomAD v4.1.1 shows numerous NMD-predicted variants distributed throughout FRYL, inconsistent with the proposed LoF-intolerance/ haploinsufficiency mechanism. (3) All the reported variants have an overall germline classification of 'Conflicting' or 'Uncertain significance' in ClinVar. (4) The fly model uses a single fry ortholog, whereas humans have two paralogs (FRY and FRYL), limiting translatability to human-specific FRYL disease (5) No familial segregation data exist (all cases simplex). (6) High rate of co-occurring candidate variants in other genes (8/14) confounds phenotype attribution. This gene has been associated with Pan-Chung-Bellen syndrome in OMIM (MIM #621049), which was last accessed on 02 September 2026. This gene is rated with 'moderate' rating on the DD panel of Gene2Phenotype, with amber rating on relevant panels in PanelApp Australia and has not been associated with any phenotypes in ClinGen. This gene is also rated amber on the Intellectual disability and Fetal anomalies panels in Genomics England PanelApp. Overall, this represents a single-publication gene-disease claim with substantive unresolved population genetics and functional modelling concerns — further independent case series and reconciliation with gnomAD v4 constraint data are needed before upgrading to green.; Changed phenotypes to: Pan-Chung-Bellen syndrome, OMIM:621049, Pan-Chung-Bellen syndrome, MONDO:0975953, FRYL-related neurodevelopmental disorder with dysmorphic facial features, with or without congenital abnormalities |
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| Skeletal dysplasia v10.6 | HSPA9 |
Ida Ertmanska gene: HSPA9 was added gene: HSPA9 was added to Skeletal dysplasia. Sources: Literature Q3_26_promote_green tags were added to gene: HSPA9. Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HSPA9 were set to 26598328; DOI:10.4172/1747-0862.1000350; 32869452; 35779070; 36052765 Phenotypes for gene: HSPA9 were set to Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801; epiphysial-vertebral-ear dysplasia-nose-plus associated findings syndrome Review for gene: HSPA9 was set to GREEN Added comment: PMID: 26598328 Royer-Bertrand et al., 2015 Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome. DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018 Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. PMID: 32869452 Younger et al., 2020 WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia. PMID: 35779070 Pacio-Miguez et al., 2022 Reported two families. F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents). PMID: 36052765 Li et al., 2022 Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora. Sources: Literature |
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| Malformations of cortical development v8.8 | ATP1A2 | Ida Ertmanska edited their review of gene: ATP1A2: Changed publications to: 33880529, 37870493, 38549198, 39046620 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.8 | ATP1A2 | Ida Ertmanska edited their review of gene: ATP1A2: Changed publications to: 33880529, 37870493 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.8 | ATP1A2 | Ida Ertmanska commented on gene: ATP1A2: Comment on mode of inheritance: While polymicrogyria is a consistent feature in patients with biallelic ATP1A2 variants, there is only 1 individual reported with polymicrogyria and a monoallelic ATP1A2 variant. Hence, the MOI should remain BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.8 | ATP1A2 |
Ida Ertmanska changed review comment from: Monoallelic cases: PMID: 33880529 Vetro et al., 2021 Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations). Additional biallelic cases: PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans. PMID: 39046620 Hassani & Malekzadeh, 2024 Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns. PMID: 38549198 Burrill et al., 2024 Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.; to: Monoallelic cases: PMID: 33880529 Vetro et al., 2021 Report of 6 patients who harboured 5 distinct heterozygous missense variants in ATP1A2. 3/6 patients had severe ID/DD, 2 - moderate, and 1 individual had no DD/ID. 2/6 patients had postnatal microcephaly. Polymicrogyria was present in just 1/6 individuals reported (P6) - more common in patients with ATP1A3 variants. Alternating hemiplegia was not present in any of the probands. Additional biallelic cases: PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans. PMID: 39046620 Hassani & Malekzadeh, 2024 Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns. PMID: 38549198 Burrill et al., 2024 Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal. |
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| Early onset or syndromic epilepsy v9.76 | ATP1A2 | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 2nd Sept 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.76 | ATP1A2 | Ida Ertmanska Phenotypes for gene: ATP1A2 were changed from Alternating hemiplegia of childhood 1, 104290; Migraine, familial basilar, 602481; Migraine, familial hemiplegic, 2, 602481; benign familial infantile convulsions; epilepsy and migraine; occipitotemporal epilepsy; infantile epileptic syndrome to Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602; fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MONDO:0859204; Developmental and epileptic encephalopathy 98, OMIM:619605; developmental and epileptic encephalopathy 98, MONDO:0030472 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.75 | ATP1A2 | Ida Ertmanska Publications for gene: ATP1A2 were set to 15159495; 29610157; 28058944; 18028407; 12953268 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.74 | ATP1A2 |
Ida Ertmanska Tag Q3_26_promote_green was removed from gene: ATP1A2. Tag Q3_26_MOI tag was added to gene: ATP1A2. |
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| Early onset or syndromic epilepsy v9.74 | ATP1A2 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ATP1A2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.74 | ATP1A2 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are now at least 7 unrelated families reported in literature with biallelic ATP1A2 variants and; to: Comment on mode of inheritance: There are now at least 7 unrelated families reported in literature with biallelic ATP1A2 variants and the 'Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies' syndrome. 2 unrelated individuals presented with epilepsy shortly after birth, and 2 further cases were reported with in-utero seizures. Hence, the mode of inheriatance should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.74 | ATP1A2 | Ida Ertmanska commented on gene: ATP1A2: Comment on mode of inheritance: There are now at least 7 unrelated families reported in literature with biallelic ATP1A2 variants and | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.74 | ATP1A2 | Ida Ertmanska edited their review of gene: ATP1A2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.8 | ATP1A2 |
Ida Ertmanska changed review comment from: Monoallelic cases: PMID: 33880529 Vetro et al., 2021 Additional biallelic cases: PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans. PMID: 39046620 Hassani & Malekzadeh, 2024 Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns. PMID: 38549198 Burrill et al., 2024 Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal.; to: Monoallelic cases: PMID: 33880529 Vetro et al., 2021 Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations). Additional biallelic cases: PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans. PMID: 39046620 Hassani & Malekzadeh, 2024 Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns. PMID: 38549198 Burrill et al., 2024 Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal. |
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| Malformations of cortical development v8.8 | ATP1A2 |
Ida Ertmanska changed review comment from: PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.; to: Monoallelic cases: PMID: 33880529 Vetro et al., 2021 Additional biallelic cases: PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans. PMID: 39046620 Hassani & Malekzadeh, 2024 Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns. PMID: 38549198 Burrill et al., 2024 Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal. |
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| Early onset or syndromic epilepsy v9.74 | ATP1A2 | Ida Ertmanska edited their review of gene: ATP1A2: Changed publications to: 28811059, 31608932, 30690204, 37870493, 38549198, 39046620 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.74 | ATP1A2 |
Ida Ertmanska changed review comment from: BIALLELIC CASES: PMID: 28811059 Wilbur et al., 2017 Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp). PMID: 31608932 Chatron et al., 2019 Report of four cases from 2 independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. Probands from both families were homozygous for unique nonsense variants in ATP1A2. PMID: 30690204 Monteiro et al., 2020 Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES. P1 & P2 - affected sibs, male and female, Brazilian. Seizures developed soon after birth in P1, and in-utero seizures suspected by the mother in P2. P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12). P1 confirmed to be homozygous for the same variant with Sanger seq, unaffected parents were het. P3 - Hispanic female neonate. Abnormal fetal movements noted, consistent with seizure activity. WES identified a homozygous ATP1A2 c.835del, p.(Arg279Glyfs*4) variant. PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans.; to: BIALLELIC CASES: PMID: 28811059 Wilbur et al., 2017 Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp). PMID: 31608932 Chatron et al., 2019 Report of four cases from 2 independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. Probands from both families were homozygous for unique nonsense variants in ATP1A2. PMID: 30690204 Monteiro et al., 2020 Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES. P1 & P2 - affected sibs, male and female, Brazilian. Seizures developed soon after birth in P1, and in-utero seizures suspected by the mother in P2. P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12). P1 confirmed to be homozygous for the same variant with Sanger seq, unaffected parents were het. P3 - Hispanic female neonate. Abnormal fetal movements noted, consistent with seizure activity. WES identified a homozygous ATP1A2 c.835del, p.(Arg279Glyfs*4) variant. PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans. PMID: 39046620 Hassani & Malekzadeh, 2024 Report of an Iranian consanguineous family with 2 newborn sibs affected by Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies 'FARIMPD' syndrome. Both passed away within the first 24 hrs after birth. Homozygous c.1234C>T, p.Arg412* variant in ATP1A2 found by WES in the newborns. PMID: 38549198 Burrill et al., 2024 Report of diamniotic twins, one of them affected. Fetal ultrasound and MRI of the affected twin demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture. The proband passed away within the first hour of life due to respiratory compromise. Postmortem trio WES identified a homozygous ATP1A2 (c.2439+1G>A) variant as causal. |
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| Early onset or syndromic epilepsy v9.74 | ATP1A2 | Ida Ertmanska edited their review of gene: ATP1A2: Changed publications to: 28811059, 31608932, 30690204, 37870493 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.74 | ATP1A2 |
Ida Ertmanska changed review comment from: BIALLELIC CASES: PMID: 28811059 Wilbur et al., 2017 Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp). PMID: 31608932 Chatron et al., 2019 Report of four cases from 2independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. PMID: 30690204 Monteiro et al., 2020 Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES. P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12).; to: BIALLELIC CASES: PMID: 28811059 Wilbur et al., 2017 Report of a boy who presented at age three months with epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. WES identified ATP1A2 comp het variants (p.Arg548Cys) & (p.Arg1008Trp). PMID: 31608932 Chatron et al., 2019 Report of four cases from 2 independent families with recessive lethal syndromic polymicrogyria. Examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. Probands from both families were homozygous for unique nonsense variants in ATP1A2. PMID: 30690204 Monteiro et al., 2020 Report of three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LoF variants in ATP1A2 were found on WES. P1 & P2 - affected sibs, male and female, Brazilian. Seizures developed soon after birth in P1, and in-utero seizures suspected by the mother in P2. P2 was homozygous for NM_000702: c.2104_2105delTG, p.(Cys702Serfs*12). P1 confirmed to be homozygous for the same variant with Sanger seq, unaffected parents were het. P3 - Hispanic female neonate. Abnormal fetal movements noted, consistent with seizure activity. WES identified a homozygous ATP1A2 c.835del, p.(Arg279Glyfs*4) variant. PMID: 37870493 Furukawa et al., 2023 Male individual born at 28 weeks, with respiratory distress and tonic seizures soon after birth. At 10 months presented with hypotonia, cryptorchidism, generalised tonic and facial clonic seizures, no eye contact or social responses. Brain MRI showed a markedly simplified gyral pattern. He was compound heterozygous for ATP1A2: c.1234C>T, p.Arg412* & ATP1A2: c.2288G>T, p.Arg763Leu - confirmed in trans. |
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| Early onset or syndromic epilepsy v9.74 | ATP1A2 | Ida Ertmanska reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28811059, 31608932, 30690204; Phenotypes: Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, OMIM:619602, fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MONDO:0859204; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.28 | DEPDC5 |
Ida Ertmanska Tag Q3_26_demote_red was removed from gene: DEPDC5. Tag Q3_26_MOI tag was added to gene: DEPDC5. |
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| Intellectual disability v11.28 | DEPDC5 |
Ida Ertmanska changed review comment from: Comment on list classification: Based on large literature reviews, intellectual disability is present in only 12-28% of individuals with DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants. Hence, this gene should be downgraded to Red on this panel; DEPDC5 is already Green on Early onset or syndromic epilepsy. As this is a demotion, an 'expert-review' tag is added to ensure NHSE agreement.; to: Comment on mode of inheritance: Based on large literature reviews, intellectual disability is present in only 12-28% of individuals with monoallelic DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants, and this gene is already Green on Early onset or syndromic epilepsy. In patients with biallelic DEPDC5 variants, developmental delay is more severe, and was the presenting feature in several cases (PMID:36067010). Hence, the MOI should be changed from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BIALLELIC, autosomal or pseudoautosomal' on this panel. As this is a demotion for monoallelic cases, an 'expert-review' tag is added to ensure NHSE agreement. |
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| Intellectual disability v11.28 | DEPDC5 | Ida Ertmanska edited their review of gene: DEPDC5: Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.28 | DEPDC5 | Ida Ertmanska Added comment: Comment on phenotypes: Phenotypes updated on 1st Sept 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.28 | DEPDC5 | Ida Ertmanska Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, OMIM:604364 to Epilepsy, familial focal, with variable foci 1, OMIM:604364; epilepsy, familial focal, with variable foci 1, MONDO:0024556; Developmental and epileptic encephalopathy 111, OMIM:620504; developmental and epileptic encephalopathy 111, MONDO:0957780 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.27 | DEPDC5 | Ida Ertmanska Publications for gene: DEPDC5 were set to 14510823; 15329069; 10825362; 10577924; 9851433; 23542701 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.26 | DEPDC5 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: DEPDC5. Tag Q3_26_demote_red tag was added to gene: DEPDC5. |
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| Intellectual disability v11.26 | DEPDC5 | Ida Ertmanska changed review comment from: Comment on list classification: Based on large literature review, intellectual disability is present in only 12-28% of individuals with DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants. Hence, this gene should be downgraded to Red on this panel; DEPDC5 is already Green on Early onset or syndromic epilepsy. As this is a demotion, an 'expert-review' tag is added to ensure NHSE agreement.; to: Comment on list classification: Based on large literature reviews, intellectual disability is present in only 12-28% of individuals with DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants. Hence, this gene should be downgraded to Red on this panel; DEPDC5 is already Green on Early onset or syndromic epilepsy. As this is a demotion, an 'expert-review' tag is added to ensure NHSE agreement. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.26 | DEPDC5 | Ida Ertmanska commented on gene: DEPDC5: Comment on list classification: Based on large literature review, intellectual disability is present in only 12-28% of individuals with DEPDC5 variants. In addition, the ID severity is usually mild, and uniformly diagnosed in patients with existing epilepsy - likely secondary to seizures. Epilepsy is the presenting feature, reported in all patients with DEPDC5 variants. Hence, this gene should be downgraded to Red on this panel; DEPDC5 is already Green on Early onset or syndromic epilepsy. As this is a demotion, an 'expert-review' tag is added to ensure NHSE agreement. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.26 | DEPDC5 | Ida Ertmanska edited their review of gene: DEPDC5: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.26 | DEPDC5 |
Ida Ertmanska edited their review of gene: DEPDC5: Added comment: https://www.ncbi.nlm.nih.gov/books/NBK385626/ - DEPDC5-Related Epilepsy entry on GeneReviews (Baulac & Baldassari, updated in 2023) states that 100% of individuals with DEPDC5-related disease present with epilepsy (most commonly frontal lobe seizures / sleep-related hypermotor epilepsy). Meanwhile, neurodevelopment and behaviour is normal in most reported cases. Intellectual disability was present in only 12% of individuals, and likely secondary to brain malfromations and infantile spasms. PMID: 41118617 Ochoa-Urrea et al., 2025 Review of 170 families with DEPDC5-Related Epilepsy. 76.1% of variant carriers developed epilepsy by age 10 years. Cortical malformations were present in 28% of those with available MRI. Early seizure onset strongly correlated with drug resistance (p = 2.4e-08), intellectual disability (p = 2.1e-08), and lesional MRI (p = 2.2e-08). Intellectual disability, usually mild, was identified in 27% of affected individuals, and psychiatric comorbidities—such as attention deficits, oppositional behaviours, mood disorders, and autism—affected 46% of the studied cohort. ID was reported exclusively in individuals with existing epilepsy.; Changed publications to: 32848577, 36067010, 41118617 |
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| Intellectual disability v11.26 | DEPDC5 |
Ida Ertmanska changed review comment from: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel: The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype. PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy. PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway. DEPDC5 is now associated with AR Developmental and epileptic encephalopathy 111, OMIM:620504, as well as AD Epilepsy, familial focal, with variable foci 1, OMIM:604364 (OMIM accessed 1st Sept 2026).; to: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel: The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype. PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy. PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway. DEPDC5 is now associated with AR Developmental and epileptic encephalopathy 111, OMIM:620504, as well as AD Epilepsy, familial focal, with variable foci 1, OMIM:604364 (OMIM accessed 1st Sept 2026). |
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| Intellectual disability v11.26 | DEPDC5 |
Ida Ertmanska changed review comment from: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel: The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype. PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy. PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway.; to: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel: The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype. PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy. PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway. DEPDC5 is now associated with AR Developmental and epileptic encephalopathy 111, OMIM:620504, as well as AD Epilepsy, familial focal, with variable foci 1, OMIM:604364 (OMIM accessed 1st Sept 2026). |
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| Intellectual disability v11.26 | DEPDC5 |
Ida Ertmanska changed review comment from: Literature review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel: The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype. PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy. PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway.; to: BIALLELIC CASES - review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Early onset or syndromic epilepsy panel: The association of monoallelic variants in DEPDC5 gene to familial focal epilepsy (MIM #604364) have already been established with previous reviews and the existence of this phenotype in both OMIM and Gene2Phenotype. PMID:32848577 reported a child with a homozygous missense variant (p.Pro1031His) who presented with cortical dysplasia and childhood onset epilepsy. PMID:36067010 reported homozygous missense variants in five unrelated families (three Irish Traveller families with same variant - p.Thr337Arg; and one Tunisian and one Lebanese families with the same variant - p.Arg806Cys). All nine children from these five families presented with consistent phenotypic features including extensive bilateral polymicrogyria, congenital macrocephaly, early onset refractory epilepsy and severe psychomotor developmental delay. Skin biopsy immunohistochemistry suggested hyperactivation of the mTOR pathway. The disease mechanism is suggested as 'loss of function' as DEPDC5 is a repressor/inhibitor within the mTOR pathway. |
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| Intellectual disability v11.26 | DEPDC5 | Ida Ertmanska reviewed gene: DEPDC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 32848577, 36067010; Phenotypes: Epilepsy, familial focal, with variable foci 1, OMIM:604364, epilepsy, familial focal, with variable foci 1, MONDO:0024556, Developmental and epileptic encephalopathy 111, OMIM:620504, developmental and epileptic encephalopathy 111, MONDO:0957780; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.74 | DEPDC5 | Ida Ertmanska Added comment: Comment on phenotypes: Recessive phenotype terms updated 1st Sept 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.74 | DEPDC5 | Ida Ertmanska Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, OMIM:604364 to Epilepsy, familial focal, with variable foci 1, OMIM:604364; epilepsy, familial focal, with variable foci 1, MONDO:0024556; Developmental and epileptic encephalopathy 111, OMIM:620504; developmental and epileptic encephalopathy 111, MONDO:0957780 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.8 | DEPDC5 | Ida Ertmanska Added comment: Comment on phenotypes: Recessive phenotype terms updated 1st Sept 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.8 | DEPDC5 | Ida Ertmanska Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, OMIM:604364; Focal cortical dysplasia to Epilepsy, familial focal, with variable foci 1, OMIM:604364; epilepsy, familial focal, with variable foci 1, MONDO:0024556; Developmental and epileptic encephalopathy 111, OMIM:620504; developmental and epileptic encephalopathy 111, MONDO:0957780 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pneumothorax - familial v3.8 | ABL1 |
Matthew Edwards gene: ABL1 was added gene: ABL1 was added to Pneumothorax - familial. Sources: NHS GMS Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ABL1 were set to PMID: 32643838; PMID: 41416177; PMID: 23826103; PMID: 33223528 Phenotypes for gene: ABL1 were set to CONGENITAL HEART DEFECTS AND SKELETAL MALFORMATIONS SYNDROME; CHDSKM Penetrance for gene: ABL1 were set to unknown Review for gene: ABL1 was set to GREEN Added comment: This gene is green on R125 FTAA panel, and several papers have pneumothorax as a presenting feature of CHDSKM (see PMIDs above). Our lab has also had a case with a pathogenic variant and pneumothorax as the primary presenting feature. Appropriate therefore for gene to be represnted on this panel. Sources: NHS GMS |
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| Arthrogryposis v10.23 | SMARCAD1 | Ida Ertmanska Classified gene: SMARCAD1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.23 | SMARCAD1 | Ida Ertmanska Added comment: Comment on list classification: There are now multiple individuals reported in literature with monoallelic SMARCAD1 variants and Basan syndrome or Huriez syndrome, both of which may include contractures. However, contractures are usually mild, e.g., only little finger affected. It is also a less prominent feature than the cutaneous symptoms. Hence, this gene should be rated Amber based on available evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.23 | SMARCAD1 | Ida Ertmanska Gene: smarcad1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.22 | SMARCAD1 | Ida Ertmanska Phenotypes for gene: SMARCAD1 were changed from Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600 to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600; isolated congenital adermatoglyphia, MONDO:0007619; absence of fingerprints-congenital milia syndrome, MONDO:0007507; palmoplantar keratoderma-sclerodactyly syndrome, MONDO:0008416 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Palmoplantar keratodermas v4.20 | SMARCAD1 | Ida Ertmanska Phenotypes for gene: SMARCAD1 were changed from Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600 to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600; isolated congenital adermatoglyphia, MONDO:0007619; absence of fingerprints-congenital milia syndrome, MONDO:0007507; palmoplantar keratoderma-sclerodactyly syndrome, MONDO:0008416 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.21 | SMARCAD1 | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes updated 28th Aug 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.21 | SMARCAD1 | Ida Ertmanska Phenotypes for gene: SMARCAD1 were changed from Basan syndrome, OMIM:129200; palmoplantar keratoderma to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600; isolated congenital adermatoglyphia, MONDO:0007619; absence of fingerprints-congenital milia syndrome, MONDO:0007507; palmoplantar keratoderma-sclerodactyly syndrome, MONDO:0008416 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.20 | SMARCAD1 | Ida Ertmanska Publications for gene: SMARCAD1 were set to 24909267; 26932190; 24664640 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.19 | SMARCAD1 | Ida Ertmanska Mode of inheritance for gene: SMARCAD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.18 | SMARCAD1 | Ida Ertmanska Classified gene: SMARCAD1 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.18 | SMARCAD1 | Ida Ertmanska Gene: smarcad1 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 | Ida Ertmanska Tag watchlist was removed from gene: SMARCAD1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 | Ida Ertmanska edited their review of gene: SMARCAD1: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 | Ida Ertmanska commented on gene: SMARCAD1: Comment on list classification: While there are numerous patients reported with variants in SMARCAD1, none of them presented with ichthyosis or erythrokeratoderma. Hence, this gene should be rated Red - 'watchlist' tag removed. Instead, this gene is proposed for promotion to Green on the Palmoplantar keratodermas panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Palmoplantar keratodermas v4.19 | SMARCAD1 | Ida Ertmanska Classified gene: SMARCAD1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Palmoplantar keratodermas v4.19 | SMARCAD1 | Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 families reported in literature with monoallelic variants in SMARCAD1 and Huriez syndrome, which includes scleroatrophy of hands and feet, as well as palmoplantar hyperkeratosis. Some individuals with Basan syndrome also presented with palmoplantar keratoderma. Both syndromes are caused by monoallelic variants (deletions and splice variants) that affect the same splice site in the short skin-specific isoform of SMARCAD1. Based on available evidence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Palmoplantar keratodermas v4.19 | SMARCAD1 | Ida Ertmanska Gene: smarcad1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Palmoplantar keratodermas v4.18 | SMARCAD1 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: SMARCAD1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Palmoplantar keratodermas v4.18 | SMARCAD1 | Ida Ertmanska edited their review of gene: SMARCAD1: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.21 | SMARCAD1 |
Ida Ertmanska gene: SMARCAD1 was added gene: SMARCAD1 was added to Arthrogryposis. Sources: Literature Mode of inheritance for gene: SMARCAD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMARCAD1 were set to 21820097; 24909267; 26932190; 29409814; 30289605; 33400266; 34909722; 35212137 Phenotypes for gene: SMARCAD1 were set to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600 Review for gene: SMARCAD1 was set to AMBER Added comment: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. Family 1 - proband had mild hyperkeratosis of soles, thin palmar skin, and weak, pointed nails. Sanger seq revealed a heterozygous 11-bp deletion in SMARCAD1: g.94253671_94253682del. Family 2 - male proband presented with scleroatrophy of hands, contracture of the little finger, sclerodactyly of distal extremities, hypoplastic nails, hypohidrosis. Proband and his affected mother were both het for a deletion affecting the SMARCAD1 donor splice site: g.94253673del Family 3 - case previously described in PMID: 8731679 Hamm, 1996 and PMID: 29409814 Günther et al., 2018 PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). Sources: Literature |
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| Palmoplantar keratodermas v4.18 | SMARCAD1 |
Ida Ertmanska gene: SMARCAD1 was added gene: SMARCAD1 was added to Palmoplantar keratodermas. Sources: Literature Mode of inheritance for gene: SMARCAD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMARCAD1 were set to 21820097; 24909267; 26932190; 29409814; 30289605; 33400266; 34909722; 35212137 Phenotypes for gene: SMARCAD1 were set to Adermatoglyphia, OMIM:136000; Basan syndrome, OMIM:129200; Huriez syndrome, OMIM:181600 Review for gene: SMARCAD1 was set to AMBER Added comment: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. Family 1 - proband had mild hyperkeratosis of soles, thin palmar skin, and weak, pointed nails. Sanger seq revealed a heterozygous 11-bp deletion in SMARCAD1: g.94253671_94253682del. Family 2 - male proband presented with scleroatrophy of hands, contracture of the little finger, sclerodactyly of distal extremities, hypoplastic nails, hypohidrosis. Proband and his affected mother were both het for a deletion affecting the SMARCAD1 donor splice site: g.94253673del Family 3 - case previously described in PMID: 8731679 Hamm, 1996 and PMID: 29409814 Günther et al., 2018 PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). Sources: Literature |
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| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 |
Ida Ertmanska changed review comment from: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. Family 1 - proband had mild hyperkeratosis of soles, thin palmar skin, and weak, pointed nails. Sanger seq revealed a heterozygous 11-bp deletion in SMARCAD1: g.94253671_94253682del. Family 2 - male proband presented with scleroatrophy of hands, contracture of the little finger, sclerodactyly of distal extremities, hypoplastic nails, hypohidrosis. Proband and his affected mother were both het for a deletion affecting the SMARCAD1 donor splice site: g.94253673del Family 3 - case previously described in PMID: 8731679 Hamm, 1996 and PMID: 29409814 Günther et al., 2018 PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). |
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| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 | Ida Ertmanska edited their review of gene: SMARCAD1: Changed rating: AMBER; Changed publications to: 21820097, 24909267, 26932190, 29409814, 30289605, 33400266, 34909722, 35212137 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 |
Ida Ertmanska changed review comment from: HURIEZ SYNDROME PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). |
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| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 | Ida Ertmanska edited their review of gene: SMARCAD1: Changed publications to: 21820097, 24909267, 26932190, 29409814, 30289605, 33400266, 34909722 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 |
Ida Ertmanska changed review comment from: HURIEZ SYNDROME PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 2 families with Huriez syndrome. SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1. Variant co-segregated with disease, maximal LOD score was 3.01. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). |
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| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 | Ida Ertmanska edited their review of gene: SMARCAD1: Changed publications to: 26932190, 29409814, 33400266 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 | Ida Ertmanska reviewed gene: SMARCAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26932190, 33400266; Phenotypes: Adermatoglyphia, OMIM:136000, Basan syndrome, OMIM:129200, Huriez syndrome, OMIM:181600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.1 | FRYL | Julie Evans reviewed gene: FRYL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.10 | PAX3 |
Ida Ertmanska changed review comment from: PMID: 34918979 Liang et al., 2021 Report of a Chinese pedigree with nonsyndromic cleft lip with or without palate. PAX3 missense variant detected: c.92C>G, p.(Thr31Ser). PMID: 27081571 Yoshida et al., 2016 Report of a 10 mo Japanese boy with pigmentation abnormalities of the right iris, ocular hypertelorism (W index: 2.00), right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. Family history of iris pigmentation abnormality and hearing loss on mother's side. Proband was het for PAX3: c.1107C>G, p.(Ser369Arg), parents not tested. Variant not in gnomAD v4.1.1. PMID: 18483623 Wu et al., 2008 - mouse model Persistent expression of Pax3 in cranial neural crest cells resulted in cleft palate, ocular defects, malformation of the sphenoid bone, and perinatal lethality in mice.; to: PMID: 34918979 Liang et al., 2021 Report of a Chinese pedigree with nonsyndromic cleft lip with or without palate. Son (proband, 11yo male) and his father affected. Both affected individuals were het for a PAX3 missense variant: c.92C>G, p.(Thr31Ser). Method: Trio WES. Variant was absent in the healthy mother, as well as 113 unrelated healthy controls. PMID: 27081571 Yoshida et al., 2016 Report of a 10 mo Japanese boy with pigmentation abnormalities of the right iris, ocular hypertelorism (W index: 2.00), right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. Family history of iris pigmentation abnormality and hearing loss on mother's side. Proband was het for PAX3: c.1107C>G, p.(Ser369Arg), parents not tested. Variant not in gnomAD v4.1.1. PMID: 18483623 Wu et al., 2008 - mouse model Persistent expression of Pax3 in cranial neural crest cells resulted in cleft palate, ocular defects, malformation of the sphenoid bone, and perinatal lethality in mice. |
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| Clefting v7.10 | PAX3 | Ida Ertmanska reviewed gene: PAX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18483623, 27081571, 34918979; Phenotypes: orofacial cleft, MONDO:0000358, Waardenburg syndrome, type 1, OMIM:193500, Waardenburg syndrome type 1, MONDO:0008670; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.32 | ATP6V0C | Ida Ertmanska changed review comment from: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients.; to: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. Ataxia has also been reported in the epilepsy/developmental cases associated with SNVs in this gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.32 | ATP6V0C | Ida Ertmanska changed review comment from: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber.; to: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v3.1 | CAV3 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CAV3. Tag Q3_26_MOI tag was added to gene: CAV3. |
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| Rhabdomyolysis and metabolic muscle disorders v6.9 | CAV3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance (1), limb girdle muscular dystrophy (1), and mild proximal muscle weakness (2). One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change.; to: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance (1), limb girdle muscular dystrophy (1), and mild proximal muscle weakness (2). One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should remain MONOALLELIC, due to conflicting evidence for a BIALLELIC association. A 'watchlist-moi' tag was added in anticipation of stronger evidence for the recessive assocation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.9 | CAV3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change.; to: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance (1), limb girdle muscular dystrophy (1), and mild proximal muscle weakness (2). One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.9 | CAV3 | Ida Ertmanska commented on gene: CAV3: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.9 | CAV3 | Ida Ertmanska Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.9 | CAV3 | Ida Ertmanska edited their review of gene: CAV3: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.9 | CAV3 |
Ida Ertmanska Tag Q3_26_MOI was removed from gene: CAV3. Tag watchlist_moi tag was added to gene: CAV3. |
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| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 | CAV3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should remain as MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. A 'watchlist-moi' tag was added in anticipation of stronger evidence for the recessive assocation.; to: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy (1 individual), and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should remain as MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. A 'watchlist-moi' tag was added in anticipation of stronger evidence for the recessive assocation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 | CAV3 | Ida Ertmanska commented on gene: CAV3: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should remain as MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. A 'watchlist-moi' tag was added in anticipation of stronger evidence for the recessive assocation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 | CAV3 | Ida Ertmanska reviewed gene: CAV3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9536092, 12666119, 15668980, 16730439, 18253147, 37166430; Phenotypes: caveolinopathy MONDO:0016146, Myopathy, distal, Tateyama type, OMIM:614321, Rippling muscle disease 2, OMIM:606072, rippling muscle disease 2, MONDO:0019947, distal myopathy, Tateyama type, MONDO:0013686; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 | CAV3 | Ida Ertmanska Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 | CAV3 |
Ida Ertmanska Tag Q3_26_MOI was removed from gene: CAV3. Tag watchlist_moi tag was added to gene: CAV3. |
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| Acute rhabdomyolysis v3.1 | CAV3 | Ida Ertmanska edited their review of gene: CAV3: Added comment: Comment on mode of inheritance: There are 7 families reported in literature with biallelic CAV3 variants and features of a metabolic muscle disorder. Only 2 patients harbouring the same variant p.Ala93Thr presented with severe rippling muscle disease (PMIDs: 12666119; 15668980). Other individuals had variable presentations including isolated exercise intolerance, limb girdle muscular dystrophy, and mild proximal muscle weakness. One individual was asymptomatic at 49 years. In addition, 2/7 cases harboured Likely Benign variants with homozygotes reported in gnomAD (PMIDs: 9536092; 18253147). Hence, mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, due to conflicting evidence for a BIALLELIC association. An 'expert-review' tag was added to obtain a second opinion on this proposed change.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v3.1 | CAV3 |
Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign.; to: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including 8 homozygotes - VUS leaning Benign. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | DCLRE1B | Ida Ertmanska Classified gene: DCLRE1B as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | DCLRE1B | Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic DCLRE1B variants and bone marrow failure, with pancytopenia or severe lymphopenia, which required transfusions early on. Additional variable features included microcephaly, IBD, and delayed speech. Only P2 had mucocutaneous features of dyskeratosis congenita, including sparse hair, leukoplakia, nail dystrophy, and skin hyperpigmentation. Based on available evidence, this gene can be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.105 | DCLRE1B | Ida Ertmanska Gene: dclre1b has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.104 | DCLRE1B | Ida Ertmanska Phenotypes for gene: DCLRE1B were changed from Dyskeratosis congenita, autosomal recessive 8, OMIM:620133 to Dyskeratosis congenita, autosomal recessive 8, OMIM:620133; dyskeratosis congenita, autosomal recessive 8, MONDO:0859319 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.103 | DCLRE1B | Ida Ertmanska Publications for gene: DCLRE1B were set to 20479256 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 | DCLRE1B | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DCLRE1B. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 | DCLRE1B | Ida Ertmanska reviewed gene: DCLRE1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 35007328; Phenotypes: Dyskeratosis congenita, autosomal recessive 8, OMIM:620133, dyskeratosis congenita, autosomal recessive 8, MONDO:0859319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.11 | ATXN1_CAG |
Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 case from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O8 (43 year old) symptomatic for SCA1 and O20 (20 years old) is pre-symptomatic . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals. 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 case from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic. |
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| Hereditary ataxia, adult onset v9.11 | ATXN1_CAG |
Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 case from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic. |
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| Hereditary spastic paraplegia, adult onset v6.14 | ATXN1_CAG | Eleanor Williams reviewed STR: ATXN1_CAG: Rating: ; Mode of pathogenicity: None; Publications: 39289638, 25344417, 36618024, 8619528; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.11 | ATXN1_CAG | Eleanor Williams Publications for STR: ATXN1_CAG were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.10 | ATXN1_CAG | Eleanor Williams reviewed STR: ATXN1_CAG: Rating: ; Mode of pathogenicity: None; Publications: 39289638, 25344417, 36618024, 8619528; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.32 | ATXN1_CAG |
Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic. |
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| Dystonia, chorea or related movement disorder, adult onset v6.9 | ATXN1_CAG |
Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years, and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic. |
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| Dystonia, chorea or related movement disorder, adult onset v6.9 | ATXN1_CAG | Eleanor Williams Publications for STR: ATXN1_CAG were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.8 | ATXN1_CAG |
Eleanor Williams edited their review of STR: ATXN1_CAG: Added comment: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; Changed publications to: 39289638, 25344417, 36618024, 8619528 |
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| Hereditary neuropathy or pain disorder v8.32 | ATXN1_CAG | Eleanor Williams Publications for STR: ATXN1_CAG were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.31 | ATXN1_CAG | Eleanor Williams reviewed STR: ATXN1_CAG: Rating: ; Mode of pathogenicity: None; Publications: 39289638, 25344417, 36618024, 8619528; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.32 | ATP6V0C | Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: ATP6V0C. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.32 | ATP6V0C | Ida Ertmanska edited their review of gene: ATP6V0C: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.32 | ATP6V0C | Ida Ertmanska Phenotypes for gene: ATP6V0C were changed from progressive ataxia and cognitive decline to Ataxia, HP:0001251 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.31 | ATP6V0C | Ida Ertmanska Mode of inheritance for gene: ATP6V0C was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.30 | ATP6V0C | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ATP6V0C. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.30 | ATP6V0C | Ida Ertmanska Tag currently-ngs-unreportable was removed from gene: ATP6V0C. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.30 | ATP6V0C | Ida Ertmanska changed review comment from: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber.; to: Comment on list classification: There are 9 unrelated families reported in literature with individuals habouring CNVs at 16p13.3, with early-onset progressive ataxia and cognitive decline. ATP6V0C is the most likely candidate gene, as it was the only one present in the minimal region of overlap for all patients. However, these structural variants would not be detected in the current NGS analysis pipeline and this gene should remain Amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.30 | ATP6V0C | Ida Ertmanska edited their review of gene: ATP6V0C: Added comment: Comment on list classification: As reviewed by Lucy Jackson, the ATP6V0C triplications can now be detected by the WGS CNV pipeline. Hence, this gene should be promoted to Green at the next update.; Changed rating: GREEN; Changed phenotypes to: Ataxia, HP:0001251 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.11 | ARPP21 | Achchuthan Shanmugasundram Classified gene: ARPP21 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.11 | ARPP21 |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two independent large-scale genetic studies (PMIDs: 38960585 & 41917433) linked ARRP21 to ALS with consistent variants (p.Pro529Leu/ p.Pro563Leu & p.Pro747Leu) and clinical severity, but no functional validation of any disease variant exists, analysis suggested variant embedded in founder-type haplotype and replication failed in Asian/Australian cohorts. ClinGen GCEP has still rated it with 'Limited' evidence, with it's last review on 14 January 2025. Hence, this gene should be rated amber with this evidence. The 'watchlist' tag has been added to re-review once functional data or a formal GCEP upgrade emerge. |
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| Neurodegenerative disorders, adult onset v9.11 | ARPP21 | Achchuthan Shanmugasundram Gene: arpp21 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.5 | PAX3 | Ida Ertmanska reviewed gene: PAX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26443304, 35607853; Phenotypes: Waardenburg syndrome, type 1, OMIM:193500, Waardenburg syndrome type 1, MONDO:0008670, Waardenburg syndrome, type 3, OMIM:148820, Waardenburg syndrome type 3, MONDO:0007862, Klein-Waardenburg syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.10 | ARPP21 | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: ARPP21. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.10 | ARPP21 | Achchuthan Shanmugasundram Publications for gene: ARPP21 were set to 8120638; 29581509; 30811981; 31653410; 3358193; 38960585; 41917433 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.9 | ARPP21 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons . This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen. Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:33581934 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons . This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen. Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.9 | ARPP21 | Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 8120638, 29581509, 30811981, 31653410, 33581934, 38960585, 41917433 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.9 | ARPP21 | Achchuthan Shanmugasundram Publications for gene: ARPP21 were set to 30811981; 38960585; 41917433 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.8 | ARPP21 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. There is some limited functional evidence available. PMID:8120638 (1994) reported that ARPP21 is predominantly expressed in a subset of brain tissues. PMID:29581509 (2018) reported that ARPP21 localises to stress granules under cellular stress, binds uridine-rich motifs in mRNA 3'UTRs via iCLIP, and acts as a positive post-transcriptional regulator (via eIF4A/eIF4G interaction) that antagonizes its co-transcribed intronic microRNA miR-128 to promote dendritic complexity in cortical neurons . This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 August 2026). But, it is classified with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen. Sources: Literature |
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| Limb disorders v9.4 | PAX3 | Ida Ertmanska Phenotypes for gene: PAX3 were changed from Waardenburg syndrome, type 3, 148820 to Waardenburg syndrome, type 1, OMIM:193500; Waardenburg syndrome type 1, MONDO:0008670; Waardenburg syndrome, type 3, OMIM:148820; Waardenburg syndrome type 3, MONDO:0007862; Klein-Waardenburg syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.3 | PAX3 | Ida Ertmanska Publications for gene: PAX3 were set to 6340503; 12949970; 7726174; 26443304; 8447316; 11683776; 30173992; 35607853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.2 | PAX3 | Ida Ertmanska edited their review of gene: PAX3: Changed publications to: 7726174, 12949970, 26443304, 35607853, 41141997, 41159045 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.2 | PAX3 | Ida Ertmanska Publications for gene: PAX3 were set to 6340503; 12949970; 7726174; 26443304; 8447316; 11683776; 30173992 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with biallelic PAX3 variants and Waardenburg syndrome type 3 / Klein syndrome. This syndrome includes limb deformities not present in patients with monoallelic PAX3 variants. Hence, the MOI should remain as BIALLELIC, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with biallelic PAX3 variants and Waardenburg syndrome type 3 / Klein syndrome. This syndrome includes limb deformities not present in patients with monoallelic PAX3 variants. Hence, the MOI should remain as BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 |
Ida Ertmanska changed review comment from: ADDITIONAL CASES SINCE 2019: PMID: 35607853 Salah et al., 2022 - biallelic case Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins. Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome. PMID: 41141997 Chen et al., 2025 Report of a proband with a deletion affecting PAX3. A detailed ultrasound examination at 14 weeks of gestation revealed no fetal anomalies. She presented with telecanthus but no pigmentary skin anomalies at birth. She developed jaundice and neonatal infection - not consistent with WS diagnosis. Isolated congenital spina bifida was noted in a previous pregnancy, terminated at 20 weeks. CMA analysis showed a 543-kb deletion in the 2q36.1 region [arr(GRCh38) 2q36.1(222,250,171_222,792,701) × 1], encompassing PAX3, FARSB, MOGAT1, and SGPP2 genes - PAX3 gene determined to explain this family's phenotypes. Deletion was confirmed to be paternally inherited. The father (I:1) displayed characteristic WS facial features (DC, synophrys, a white forelock, and a broad nasal root) but had normal hearing, intellectual ability, and growth. PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).; to: ADDITIONAL CASES SINCE 2019: PMID: 35607853 Salah et al., 2022 - biallelic case Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins. Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome. PMID: 41141997 Chen et al., 2025 - het deletion Report of a proband with a deletion affecting PAX3. A detailed ultrasound examination at 14 weeks of gestation revealed no fetal anomalies. She presented with telecanthus but no pigmentary skin anomalies at birth. She developed jaundice and neonatal infection - not consistent with WS diagnosis. Isolated congenital spina bifida was noted in a previous pregnancy, terminated at 20 weeks. CMA analysis showed a 543-kb deletion in the 2q36.1 region [arr(GRCh38) 2q36.1(222,250,171_222,792,701) × 1], encompassing PAX3, FARSB, MOGAT1, and SGPP2 genes - PAX3 gene determined to explain this family's phenotypes. Deletion was confirmed to be paternally inherited. The father (I:1) displayed characteristic WS facial features (DC, synophrys, a white forelock, and a broad nasal root) but had normal hearing, intellectual ability, and growth. PMID: 41159045 Zafiri et al., 2025 - het missense variant Report of a 33yo male patient with WS type 1: white forelock, skin depigmentation (white patches on the abdoment), severe neurosensory hearing loss. A c.209G>A (p.Cys70Tyr) variant was detected in the PAX3 gene in heterozygosity. Father and brother were het for the same change, but had normal hearing, with only a white forelock noted in the brother. PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026). |
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| Limb disorders v9.1 | PAX3 |
Ida Ertmanska changed review comment from: PMID: 7726174 Zlotogora et al. 1995 Report of a large kindred with Waardenburg syndrome type 1 and a heterozygous mutation S84F in PAX3 gene. 1 child, born of consanguineous parents, had a severe phenotype consistent with WS type 3. This child was homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Severe changes were present in the upper limbs, with rigidity of the larger joints -including shoulders, elbows, and wrists-as well as of the smaller joints of the fingers. Muscle wasting was severe in the pectoral region, the shoulders, and upper limbs. Axillary webs were present on both sides. There was a slight degree of contracture of the knees, and there was calcaneovalgus deformation of the feet. PMID: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het). PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins. Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome. PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).; to: ADDITIONAL CASES SINCE 2019: PMID: 35607853 Salah et al., 2022 - biallelic case Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins. Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome. PMID: 41141997 Chen et al., 2025 Report of a proband with a deletion affecting PAX3. A detailed ultrasound examination at 14 weeks of gestation revealed no fetal anomalies. She presented with telecanthus but no pigmentary skin anomalies at birth. She developed jaundice and neonatal infection - not consistent with WS diagnosis. Isolated congenital spina bifida was noted in a previous pregnancy, terminated at 20 weeks. CMA analysis showed a 543-kb deletion in the 2q36.1 region [arr(GRCh38) 2q36.1(222,250,171_222,792,701) × 1], encompassing PAX3, FARSB, MOGAT1, and SGPP2 genes - PAX3 gene determined to explain this family's phenotypes. Deletion was confirmed to be paternally inherited. The father (I:1) displayed characteristic WS facial features (DC, synophrys, a white forelock, and a broad nasal root) but had normal hearing, intellectual ability, and growth. PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026). |
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| Neurodegenerative disorders, adult onset v9.8 | ARPP21 | Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 8120638, 29581509, 30811981, 31653410, 3358193, 38960585, 41917433 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.8 | ARPP21 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Note that p.Pro529Leu is also annotated as p.Pro563Leu depending on transcript build (as in ClinGen curation - https://search.clinicalgenome.org/CCID:004177). The p.Pro563Leu variant is present in only 4 alleles in gnomAD v4.1.1. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. PMID:3358193 (2021) screened 81 familial and 618 sporadic Australian ALS cases and found no significant enrichment of protein-altering variants in either GLT8D1 or ARPP21 genes. PMID:38960585 (2025) reported the identification of the same heterozygous ARPP21 missense variant (p.Pro529Leu/ p.Pro563Leu) in 10 affected individuals across seven unrelated ALS families, all with a classic spinal- or bulbar-onset ALS phenotype, and no variants were found in other ALS genes. Haplotype analysis suggested that the variant is embedded in a founder-type haplotype enriched in Iberian/British/South Asian ancestries and rare in East Asian/African ancestries, which the authors propose explains non-replication in other populations. PMID:41917433 (2026) harmonized and analyzed exome data from 22 cohorts, totaling 17,919 individuals with ALS and 200,703 controls across discovery and replication phases, which independently replicated p.Pro563Leu as an ALS-associated variant after excluding overlapping UK/Spanish carriers (meta P=4.31×10⁻⁹, OR 44.8) and identified a novel second variant p.Pro747Leu (OR 75.8, not previously reported). The p.Pro747Leu variant is found in eight alleles in gnomAD v4.1.1. Sources: Literature |
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| Limb disorders v9.1 | PAX3 | Ida Ertmanska edited their review of gene: PAX3: Changed publications to: 7726174, 12949970, 26443304, 35607853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 |
Ida Ertmanska changed review comment from: PMID: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het). PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins. Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome. PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).; to: PMID: 7726174 Zlotogora et al. 1995 Report of a large kindred with Waardenburg syndrome type 1 and a heterozygous mutation S84F in PAX3 gene. 1 child, born of consanguineous parents, had a severe phenotype consistent with WS type 3. This child was homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Severe changes were present in the upper limbs, with rigidity of the larger joints -including shoulders, elbows, and wrists-as well as of the smaller joints of the fingers. Muscle wasting was severe in the pectoral region, the shoulders, and upper limbs. Axillary webs were present on both sides. There was a slight degree of contracture of the knees, and there was calcaneovalgus deformation of the feet. PMID: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het). PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins. Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome. PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026). |
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| Limb disorders v9.1 | PAX3 | Ida Ertmanska commented on gene: PAX3: Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with biallelic PAX3 variants and Waardenburg syndrome type 3 / Klein syndrome. This syndrome includes limb deformities not present in patients with monoallelic PAX3 variants. Hence, the MOI should remain as BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 | Ida Ertmanska edited their review of gene: PAX3: Changed rating: GREEN; Changed publications to: 12949970 26443304, 35607853; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | PAX3 |
Ida Ertmanska changed review comment from: PMID: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for p.Y90H PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins. Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome. PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026).; to: PMID: 12949970 Wollnik et al., 2003 Report of an 18-months old Turkish proband with Waardenburg syndrome, type 3: dystopia canthorum, partial albinism, skin depigmentation, and upper-limb defects (contractures, ulnar deviation, minimal webbing). Consanguineous parents both have Waardenburg syndrome, type 1 (no upper limb anomalies or abnormal skin pigmentation). PAX3 sequencing showed the proband was homozygous for c.268T>C, p.Tyr90His (parents both het). PMID: 26443304 Mousty et al., 2015 Proband with Waardenburg syndrome type 3 (also known as Klein-Waardenburg syndrome) with a prenatal diagnosis. Ultrasound revealed cystic hygroma, holoprosencephaly, lack of active movements, and limb abnormalities (short long bones, bilateral club foot and club hand). Pregnancy was terminated at 13 weeks. PAX3 sequencing revealed a c.807C>G, p.Asn269Lys variant, homozygous in the fetus and het in both parents. Second pregnancy also terminated at 14 weeks, given the same ultrasound profile - fetus confirmed to be homozygous for the same variant. Parents are firs cousins, French, both presenting with Waardenburg syndrome type 1: dystopia canthorum, early graying, sensorineural deafness; no depigmentation or muscoskeletal anomalies noted. PMID: 35607853 Salah et al., 2022 Report of a severely affected female child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe). Method: clinical Sanger seq of PAX3. Antenatal scan showed open spina bifida and limb deformities. Proband presented at birth with severe pigmentary skin defects, facial dysmorphism, muscle wasting, joint contractures. Brain CT scan revealed cerebellum and medulla displacement. She died at the age of 11 months. Family history included several family members with Waardenburg syndrome type 1. Parents are consanguineous, of Palestinian Arab origins. Authors highlight that patients with monoallelic variants should be diagnosed with Waardenburg syndrome, while biallelic variants result in a separate disease entity of Klein syndrome. PAX3 is associated with AD Waardenburg syndrome, type 1, OMIM:193500, AD Craniofacial-deafness-hand syndrome, OMIM:122880. and AD, AR Waardenburg syndrome, type 3, OMIM:148820 (OMIM accessed 24th Aug 2026). |
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| Limb disorders v9.1 | PAX3 | Ida Ertmanska reviewed gene: PAX3: Rating: ; Mode of pathogenicity: None; Publications: 26443304, 35607853; Phenotypes: Waardenburg syndrome, type 1, OMIM:193500, Waardenburg syndrome type 1, MONDO:0008670, Waardenburg syndrome, type 3, OMIM:148820, Waardenburg syndrome type 3, MONDO:0007862, Klein-Waardenburg syndrome; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.8 | ARPP21 | Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 30811981, 31653410, 3358193, 38960585, 41917433 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.8 | ARPP21 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Sources: Literature; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. PMID:31653410 (2019) reported the analysis of rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China, where they did not find any significant association between ALS and GLT8D1 or ARPP21. Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.8 | ARPP21 | Achchuthan Shanmugasundram edited their review of gene: ARPP21: Changed publications to: 30811981, 31653410, 38960585, 41917433 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.8 | ARPP21 |
Achchuthan Shanmugasundram gene: ARPP21 was added gene: ARPP21 was added to Neurodegenerative disorders, adult onset. Sources: Literature Mode of inheritance for gene: ARPP21 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARPP21 were set to 30811981; 38960585; 41917433 Phenotypes for gene: ARPP21 were set to amyotrophic lateral sclerosis, MONDO:0004976 Review for gene: ARPP21 was set to AMBER Added comment: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients, of which three of them also had p.Pro529Leu in ARPP21, and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort identified four additional patients with p.Pro529Leu variant in ARPP21, but not with any variants in GLT8D1 gene. Sources: Literature |
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| Hereditary neuropathy or pain disorder v8.31 | COL6A3 | Luke Stuart reviewed gene: COL6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 42520849; Phenotypes: Motor peripheral neuropathy, MONDO:0002316; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.26 | RIC1 | Ida Ertmanska Publications for gene: RIC1 were set to 31932796; 27878435 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.25 | RIC1 | Ida Ertmanska commented on gene: RIC1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.13 | RIC1 | Ida Ertmanska changed review comment from: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family with a founder variant, plus a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.; to: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family with a founder variant, plus a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BIALLELIC, autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.13 | RIC1 | Ida Ertmanska Publications for gene: RIC1 were set to 27878435; 31932796 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.12 | RIC1 | Ida Ertmanska Phenotypes for gene: RIC1 were changed from CATIFA syndrome 618761 to CATIFA syndrome, OMIM:618761; Catifa syndrome, MONDO:0032901 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.11 | RIC1 | Ida Ertmanska commented on gene: RIC1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.23 | UQCC1 | Ida Ertmanska Mode of inheritance for gene: UQCC1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.23 | UQCC1 | Ida Ertmanska Tag watchlist tag was added to gene: UQCC1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.23 | UQCC1 | Ida Ertmanska Classified gene: UQCC1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.23 | UQCC1 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases. MOI set to BOTH for the moment, as it is not clear what mode is correct here. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.23 | UQCC1 | Ida Ertmanska Gene: uqcc1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.22 | UQCC1 |
Ida Ertmanska commented on gene: UQCC1: PMID: 39504961 AlAbdi et al., 2025 Study of a large exome/genome dataset - Arab population, 17,592 local exomes and 768 local genomes. A founder variant in UQCC1 (NM_018244.5:c.656T>A;p.(Ile219Asn)) was identified in two Arab families with lactic acidosis and borderline microcephaly. Diagnosed with 'UQCC1-related mitochondrial energy disorder'. 1 individual was homozygous, and 3 heterozygous for the variant (presuming all 4 are affected?). No segregation or functional evidence provided. |
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| Mitochondrial disorders v10.22 | UQCC1 | Ida Ertmanska Mode of inheritance for gene: UQCC1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.21 | UQCC1 | Ida Ertmanska Publications for gene: UQCC1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.20 | UQCC1 | Ida Ertmanska Added comment: Comment on phenotypes: No OMIM phenotype associated as of 20th Aug 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.20 | UQCC1 | Ida Ertmanska Phenotypes for gene: UQCC1 were changed from No OMIM phenotype to mitochondrial respiratory chain complex deficiency, MONDO:0000066 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.22 | UQCC1 | Ida Ertmanska Added comment: Comment on phenotypes: No OMIM phenotype associated as of 20th Aug 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.22 | UQCC1 | Ida Ertmanska Phenotypes for gene: UQCC1 were changed from mitochondrial respiratory chain complex deficiency, MONDO:0000066 to mitochondrial respiratory chain complex deficiency, MONDO:0000066 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.21 | UQCC1 | Ida Ertmanska Phenotypes for gene: UQCC1 were changed from No OMIM phenotype to mitochondrial respiratory chain complex deficiency, MONDO:0000066 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.20 | UQCC1 | Ida Ertmanska Publications for gene: UQCC1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.19 | UQCC1 | Ida Ertmanska Classified gene: UQCC1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.19 | UQCC1 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases. MOI set to BOTH for the moment, as it is not clear what mode is correct here. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.19 | UQCC1 | Ida Ertmanska Gene: uqcc1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.18 | UQCC1 | Ida Ertmanska Tag watchlist tag was added to gene: UQCC1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.18 | UQCC1 | Ida Ertmanska reviewed gene: UQCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24385928, 39504961; Phenotypes: mitochondrial respiratory chain complex deficiency, MONDO:0000066; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.14 | UQCC1 | Ida Ertmanska Tag watchlist tag was added to gene: UQCC1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.14 | UQCC1 | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases.; to: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases. MOI set to BOTH for the moment, as it is not clear what mode is correct here. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.14 | UQCC1 | Ida Ertmanska Classified gene: UQCC1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.14 | UQCC1 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Hannah Robinson, there are now 2 related families reported with a founder UQCC1 missense variant. There are also supportive functional studies. Hence, this gene can be rated Amber. A 'watchlist' tag was added in anticipation of further cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.14 | UQCC1 | Ida Ertmanska Gene: uqcc1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.13 | UQCC1 | Ida Ertmanska Mode of inheritance for gene: UQCC1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.12 | UQCC1 | Ida Ertmanska Added comment: Comment on phenotypes: No OMIM phenotype associated as of 20th Aug 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.12 | UQCC1 | Ida Ertmanska Phenotypes for gene: UQCC1 were changed from mitochondrial respiratory chain complex deficiency, MONDO:0000066 to mitochondrial respiratory chain complex deficiency, MONDO:0000066 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.11 | UQCC1 | Ida Ertmanska Phenotypes for gene: UQCC1 were changed from No OMIM phenotype to mitochondrial respiratory chain complex deficiency, MONDO:0000066 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.10 | UQCC1 | Ida Ertmanska Publications for gene: UQCC1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.9 | UQCC1 |
Ida Ertmanska changed review comment from: PMID: 39504961 AlAbdi et al., 2025 Study of a large exome/genome dataset - Arab population, 17,592 local exomes and 768 local genomes. A founder variant in UQCC1 (NM_018244.5:c.656T>A;p.(Ile219Asn)) was identified in two Arab families with lactic acidosis and borderline microcephaly. Diagnosed with 'UQCC1-related mitochondrial energy disorder'. 1 individual was homozygous, and 3 heterozygous for the variant (presuming all 4 are affected?). No segregation or functional evidence provided.; to: PMID: 39504961 AlAbdi et al., 2025 Study of a large exome/genome dataset - Arab population, 17,592 local exomes and 768 local genomes. A founder variant in UQCC1 (NM_018244.5:c.656T>A;p.(Ile219Asn)) was identified in two Arab families with lactic acidosis and borderline microcephaly. Diagnosed with 'UQCC1-related mitochondrial energy disorder'. 1 individual was homozygous, and 3 heterozygous for the variant (presuming all 4 are affected?). No segregation or functional evidence provided. |
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| Mitochondrial disorder with complex III deficiency v2.9 | UQCC1 | Ida Ertmanska edited their review of gene: UQCC1: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.9 | UQCC1 | Ida Ertmanska reviewed gene: UQCC1: Rating: RED; Mode of pathogenicity: None; Publications: 39504961; Phenotypes: mitochondrial respiratory chain complex deficiency, MONDO:0000066; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.11 | RIC1 |
Luke Stuart changed review comment from: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026). Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate. Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. 7/8 patients ahd cataract. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect. Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded. Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting, as well as in structural brain development. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating for bilateral congenital cataracts is reiterated.; to: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026). Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate. Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. 7/8 patients had cataract. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect. Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded. Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting, as well as in structural brain development. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating for bilateral congenital cataracts is reiterated. |
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| Intellectual disability v11.25 | RIC1 | Luke Stuart reviewed gene: RIC1: Rating: ; Mode of pathogenicity: None; Publications: 27878435, 31932796, 36493769; Phenotypes: CATIFA syndrome, OMIM:618761, Catifa syndrome, MONDO:0032901; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.11 | RIC1 |
Luke Stuart changed review comment from: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026). Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate. Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect. Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded. Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating for intellectual disability is reiterated.; to: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026). Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate. Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. 7/8 patients ahd cataract. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect. Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded. Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting, as well as in structural brain development. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating for bilateral congenital cataracts is reiterated. |
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| Bilateral congenital or childhood onset cataracts v8.11 | RIC1 | Luke Stuart reviewed gene: RIC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27878435, 31932796, 36493769; Phenotypes: CATIFA syndrome, OMIM:618761, Catifa syndrome, MONDO:0032901; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.18 | PTPRO |
Luke Stuart changed review comment from: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026) Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858). Wharram et al., 2000 (PMID 11086029): Ptpro-/- mice show altered podocyte structure- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by scanning and transmission electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and a filtration/pressure regulation defect rather than overt proteinuria in mice.; to: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026) Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858). Wharram et al., 2000 (PMID 11086029): Ptpro-/- mice show altered podocyte structure, consistent with human disease subjects- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and might reduce renal functional reserve. An amber rating with watchlist designation is appropriate, given 2 unrelated families with segregation, plus an animal model partially recapitulating the phenotype seen in humans disease subjects. |
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| Clefting v7.10 | RIC1 | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family, with a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.; to: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family with a founder variant, plus a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.10 | RIC1 | Ida Ertmanska Tag founder-effect tag was added to gene: RIC1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.25 | RIC1 | Ida Ertmanska Phenotypes for gene: RIC1 were changed from CATIFA syndrome 618761; Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD to CATIFA syndrome, OMIM:618761; Catifa syndrome, MONDO:0032901 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.10 | RIC1 | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 consanguineous family, with a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases.; to: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 extended consanguineous family, with a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.10 | RIC1 | Ida Ertmanska Tag watchlist tag was added to gene: RIC1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.10 | RIC1 | Ida Ertmanska Classified gene: RIC1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.10 | RIC1 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there is emerging evidence for RIC1 association with CATIFA syndrome, which includes clefting, in individuals with biallelic variants (1 consanguineous family, with a supportive functional model). Non-syndromic clefting was reported in 3 individuals with monoallelic variants, though little variant and clinical detail was provided. Xenopus and zebrafish knock-down model also support this association. Based on available evidence, this gene can be rated Amber, with MOI set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. A 'watchlist' tag was added in anticipation of further cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.10 | RIC1 | Ida Ertmanska Gene: ric1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.24 | GIGYF1 | Achchuthan Shanmugasundram Publications for gene: GIGYF1 were set to 33057194; 35917186; 36924980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.23 | GIGYF1 |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene is identified with significant enrichment in multiple large cohorts of autism spectrum disorder patients. Detailed clinical information was only available for a small subset of patients, from which intellectual disability was reported in 11/25 patients. However, severity of ID was not provided for any of these patients. Hence, this gene is rated amber with 'watchlist' tag added.; to: Comment on list classification: GIGYF1 shows statistically robust de novo enrichment for a complex neurodevelopmental disorder across three large cohorts of autism spectrum disorder patients (PMID:33057194, PMID:35917192, PMID:36924980), with supporting functional data in cell and animal models. However, only 25 individuals across the literature have detailed clinical phenotyping, of whom 11 had confirmed ID (no severity reported). Although ClinGen rated it 'Definitive' for complex neurodevelopmental disorder, ClinGen's own review flags unresolved penetrance given recurrence of variants in unaffected parents/population controls. Gene2Phenotype recently downgraded this gene from 'moderate' to 'limited' confidence on the DD panel, and OMIM has no phenotype association as of August 2026. Hence, this gene is rated amber based on all these evidences. The 'watchlist' tag has been added as recommendation for re-review as additional deeply phenotyped ID/GDD cases are published. |
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| Clefting v7.9 | RIC1 |
Luke Stuart gene: RIC1 was added gene: RIC1 was added to Clefting. Sources: Literature Mode of inheritance for gene: RIC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: RIC1 were set to 27878435; 31932796; 36493769 Phenotypes for gene: RIC1 were set to CATIFA syndrome, OMIM:618761; Catifa syndrome, MONDO:0032901 Review for gene: RIC1 was set to AMBER Added comment: RIC1 is associated with autosomal recessive CATIFA syndrome (OMIM #618761; accessed 08/2026). Patel et al., 2017 (PMID 27878435) reported two unrelated males from consanguineous families who were homozygous for the same founder variant, RIC1 p.Arg1265Pro (R1265P), within a shared autozygous interval. Both had syndromic cataracts with global developmental delay, microcephaly, and structural brain anomalies detectable on MRI, with variable cleft lip and palate. Unlu et al., 2020 (PMID 31932796) described eight additional affected individuals from the same extended familes, all homozygous for RIC1 p.Arg1265Pro (affecting the final coding residue of exon 24). Phenotypes included global developmental delay, intellectual disability, motor, speech and cognitive impairment, hypotonia with clumsy gait, variable craniofacial dysmorphism, tooth eruption/alignment abnormalities, and cleft lip and/or palate in 5/8 individuals. Behavioural abnormalities and ADHD were reported in all seven affected males. In zebrafish, ric1−/− animals showed intracellular collagen retention, defective cartilage matrix formation, craniofacial malformations, tooth defects, tendon and muscle attachment abnormalities, impaired locomotion, and reduced forebrain and cerebellar structures. Wild-type human RIC1 rescued collagen secretion and craniofacial defects, whereas RIC1 p.Arg1265Pro failed to do so effectively. cDNA analysis of patient fibroblasts identified two distinct transcripts: one correctly spliced transcript encoding the p.Arg1265Pro variant, and a second transcript with intron 24 retention, introducing a premature stop codon at position 1266 and predicted to undergo NMD. Fibroblasts from CATIFA patients also had reduced levels of RIC1 transcript (<50% of control cells), supporting a hypomorphic splicing defect. Landson et al., 2023 (PMID 36493769) reported three individuals with non-syndromic cleft lip/palate carrying a deletion encompassing the RIC1 5′UTR and exons 1–2. Inheritance data were available for two individuals: one deletion occurred de novo and one was inherited from an affected mother. In Xenopus (splice-blocking morpholino knockdown and F0 CRISPR knockout) and zebrafish (F0 CRISPR knockout), loss of ric1 caused cleft-like midfacial defects and hypoplastic jaw cartilages. Sequencing was not performed, thus the presence of a second pathogenic hit on the non-deleted allele cannot be excluded. Summary: Homozygosity for the founder variant p.Arg1265Pro segregated with CATIFA syndrome in a large consanguineous family. Functional studies in zebrafish and Xenopus support a role for RIC1 in craniofacial development and clefting. Additional evidence suggests a possible association between heterozygous loss of RIC1 (haploinsufficiency) and non-syndromic cleft lip/palate. An amber rating with BOTH monoallelic and biallelic inheritance is recommended for clefting. Sources: Literature |
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| Intellectual disability v11.23 | GIGYF1 |
Achchuthan Shanmugasundram changed review comment from: PMID:33057194 (2020) - This gene has been identified with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). PMID:35917186 (2022) - 60 individuals carrying 35 distinct GIGYF1 likely gene-disruptive (LGD) variants, identified from SPARK/SSC autism cohorts (20,452 trios + 12,227 singletons) plus 7 additional GeneMatcher-ascertained probands. This cohort was ascertained specifically through ASD registries, so detailed non-ASD clinical/developmental phenotyping (including formal ID assessment) was not systematically reported for most of the 60 individuals. However, detailed clinical information was available for 11 patients, of which 9 patients had ASD, 10 had speech-language issues, 3 had motor delays, and 6 had ID. Severity of ID has not been provided for any of these patients. PMID:36924980 (2023) - 26 de novo variants identified across a combined 44,665 NDD trios (ASD-primary and DD-primary cohorts). Of these, detailed clinical information was obtained for only 14 probands, of which 12 had ASD, 5 had DD, 5 had ID, 3 had motor delay and 8 had speech delay. Severity of ID has not been provided for any of these patients. This gene has not yet been associated with any relevant phenotype in OMIM (last accessed 16 August 2026), but associated with GIGYF1-related developmental disorder with 'limited' rating on the DD panel of Gene2Phenotype. This gene has been associated with 'Definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Intellectual Disability and Autism GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009351).; to: PMID:33057194 (2020) - This gene has been identified with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 14 de novo variants (4 frameshift, 5 missense, 1 splice donor, 3 stopgain, 1 synonymous) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). PMID:35917186 (2022) - 60 individuals carrying 35 distinct GIGYF1 likely gene-disruptive (LGD) variants, identified from SPARK/SSC autism cohorts (20,452 trios + 12,227 singletons) plus 7 additional GeneMatcher-ascertained probands. This cohort was ascertained specifically through ASD registries, so detailed non-ASD clinical/developmental phenotyping (including formal ID assessment) was not systematically reported for most of the 60 individuals. However, detailed clinical information was available for 11 patients, of which 9 patients had ASD, 10 had speech-language issues, 3 had motor delays, and 6 had ID. Severity of ID has not been provided for any of these patients. PMID:36924980 (2023) - 26 de novo variants identified across a combined 44,665 NDD trios (ASD-primary and DD-primary cohorts). Of these, detailed clinical information was obtained for only 14 probands, of which 12 had ASD, 5 had DD, 5 had ID, 3 had motor delay and 8 had speech delay. Severity of ID has not been provided for any of these patients. The pLI = 0 in gnomAD v4.1.1 for GIGYF indicating lack of constraint against LOF. This gene has not yet been associated with any relevant phenotype in OMIM (last accessed 16 August 2026), but associated with GIGYF1-related developmental disorder with 'limited' rating on the DD panel of Gene2Phenotype. This gene was previously rated 'moderate/ on the DD panel in G2P and has been demoted in the last year. This gene has been associated with 'Definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Intellectual Disability and Autism GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009351). However, ClinGen review noted that individuals with similar variants have also been observed in the general population or in reportedly unaffected parents of affected individuals, and deep phenotyping of parents in these studies is often unavailable. In addition, the extent of reduced penetrance and variable expressivity is currently unknown (PMID:35917186). |
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| Nephrocalcinosis or nephrolithiasis v6.3 | ABCC6 |
John Sayer gene: ABCC6 was added gene: ABCC6 was added to Nephrocalcinosis or nephrolithiasis. Sources: Other Mode of inheritance for gene: ABCC6 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ABCC6 were set to PMID: 41908612; 33820832 Phenotypes for gene: ABCC6 were set to nephrolithiasis; nephrocalcinosis Penetrance for gene: ABCC6 were set to Incomplete Review for gene: ABCC6 was set to GREEN Added comment: ABCC6 causes autosomal recessive pseudoxanthoma elasticum which can include vascular and tissue calcification including kidney Emergin evidence of het carriers with nephrolithiasis and nephrocalcinosis phenotypes. Sources: Other |
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| Leukodystrophy, adult onset v7.9 | CTSA | Lauren Turton reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.18 | NUP205 | Ida Ertmanska Mode of pathogenicity for gene: NUP205 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.17 | NUP205 | Ida Ertmanska Mode of pathogenicity for gene: NUP205 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.5 | MMP9 | Ida Ertmanska Tag Q3_26_promote_green was removed from gene: MMP9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.5 | MMP9 | Ida Ertmanska Publications for gene: MMP9 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.4 | MMP9 | Ida Ertmanska Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.4 | MMP9 | Ida Ertmanska Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.16 | PTPRO |
Luke Stuart changed review comment from: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026) Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858). Ptpro-/- mice show altered podocyte structure- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by scanning and transmission electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and a filtration/pressure regulation defect rather than overt proteinuria in mice.; to: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026) Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858). Wharram et al., 2000 (PMID 11086029): Ptpro-/- mice show altered podocyte structure- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by scanning and transmission electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and a filtration/pressure regulation defect rather than overt proteinuria in mice. |
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| Proteinuric renal disease v6.16 | PTPRO |
Luke Stuart changed review comment from: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026) Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858).; to: PTPRO is associated with Nephrotic syndrome, type 6 #614196 (AR) in OMIM (accessed 08/2026) Thakor et al., 2021 (PMID 34546508) screened seven podocyte/nephrotic-syndrome-associated genes (TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2) in 90 Indian patients with steroid-sensitive (SSNS) and steroid-resistant (SRNS) nephrotic syndrome. They identified two likely pathogenic PTPRO variants (c.1778T>C p.(Val593Ala) and c.*16A>G) in SNSS patients. Methodology states classification was via ACMG standards, though the assertion criteria are not provided, and no clinvar nor LOVD record for either variant could be found. Supplemental table 2 suggests both variants were found in the heterozygous state, at odds with the proposed autosomal recessive inheritance mechanism in the primary case report by Ozaltin et al., 2011 (PMID 21722858). Ptpro-/- mice show altered podocyte structure- foot processes are shorter, broader and distribution of the cytoskeletal protein vimentin is altered, confirmed by scanning and transmission electron microscopy. These structural changes were accompanied by reduced glomerular nephrin content and a measurable reduction in glomerular filtration rate, along with a predisposition to hypertension after nephrectomy. Notably, baseline Ptpro-/- mice did not show increased albuminuria under normal conditions, indicating GLEPP1 (encoded by Ptpro) loss alone produces subclinical structural podocyte anomalies and a filtration/pressure regulation defect rather than overt proteinuria in mice. |
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| Proteinuric renal disease v6.16 | PTPRO | Luke Stuart reviewed gene: PTPRO: Rating: AMBER; Mode of pathogenicity: None; Publications: 34546508, 21722858; Phenotypes: Nephrotic syndrome, type 6, OMIM:614196; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.7 | ROBO2 | Ida Ertmanska Publications for gene: ROBO2 were set to 27002985; 29194579; 32041992; 34059960 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.6 | ROBO2 | Ida Ertmanska edited their review of gene: ROBO2: Changed publications to: 17357069, 23536131, 26026792, 27002985, 29194579, 32041992, 34059960 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.6 | ROBO2 |
Ida Ertmanska changed review comment from: PMID: 34059960 Liu et al., 2021 Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux. Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1) Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1) Both classified VUS in the paper according to ACMG criteria. PMID: 32041992 Darlow et al., 2020 Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants. Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2. PMID: 29194579 Rasmussen et al., 2018 Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect. PMID: 27002985 Mitsioni et al., 2016 103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were NOT found to be associated with nonsyndromic VUR or VUR-RHD. PMID: 24429398 Hwang et al., 2014 Cohort of 749 individuals from 650 different families with CAKUT, mostly from Eastern Europe (63%). 4 families had variants in ROBO2 - 2 of Indian origin, and 2 Eastern European. 4 unique ROBO2 missense variants were detected. Specific diagnoses of the 4 probands included Multicystic dysplastic kidney, Posterior urethral valves, Vesicoureteral reflux, and Ureteropelvic junction obstruction. ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026).; to: PMID: 34059960 Liu et al., 2021 Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux. Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1) Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1) Both classified VUS in the paper according to ACMG criteria. PMID: 32041992 Darlow et al., 2020 Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants. Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2. PMID: 29194579 Rasmussen et al., 2018 Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect. PMID: 27002985 Mitsioni et al., 2016 103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were not found to be associated with nonsyndromic VUR or VUR-RHD in this cohort. PMID: 24429398 Hwang et al., 2014 Cohort of 749 individuals from 650 different families with CAKUT, mostly from Eastern Europe (63%). 4 families had variants in ROBO2 - 2 of Indian origin, and 2 Eastern European. 4 unique ROBO2 missense variants were detected. Specific diagnoses of the 4 probands included Multicystic dysplastic kidney, Posterior urethral valves, Vesicoureteral reflux, and Ureteropelvic junction obstruction. PMID: 23536131 Dobson et al., 2013 'Heterozygous non-synonymous ROBO2 variants are unlikely to be sufficient to cause familial vesicoureteric reflux'. Sequenced 227 index cases with primary VUR in an Irish population and found ROBO2 55 variants, of which 20 were novel. Only p.Pro522Thr and p.Val799Ile segregated with the disorder. Authors pose ROBO2 variants are more likely to act as modifiers, causing VUR with digenic or oligogenic inheritance. PMID: 17357069 - Lu et al., 2007 Report of a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2. FUNCTIONAL EVIDENCE: Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage exhibit striking CAKUT-VUR phenotypes. Robo2del5/del5 homozygotes uniformly died shortly after birth with multiplex, dysplastic kidneys and short ureters. 4 (15%) of 26 Robo2del5/+ heterozygous newborns exhibited a unilateral CAKUT-VUR phenotype. With gene dosage reduced further, up to 40-70% of the heterozygous knock-down mice exhibited CAKUT-VUR. ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026). ROBO2 is also Green on Congenital anomalies of the kidney and urinary tract (CAKUT) in PanelApp Australia (accessed 17th Aug 2026). |
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| Unexplained young onset end-stage renal disease - additional genes v2.6 | ROBO2 |
Ida Ertmanska changed review comment from: PMID: 34059960 Liu et al., 2021 Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux. Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1) Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1) Both classified VUS in the paper according to ACMG criteria. PMID: 32041992 Darlow et al., 2020 Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants. Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2. PMID: 29194579 Rasmussen et al., 2018 Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect. PMID: 27002985 Mitsioni et al., 2016 103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were NOT found to be associated with nonsyndromic VUR or VUR-RHD. ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026).; to: PMID: 34059960 Liu et al., 2021 Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux. Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1) Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1) Both classified VUS in the paper according to ACMG criteria. PMID: 32041992 Darlow et al., 2020 Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants. Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2. PMID: 29194579 Rasmussen et al., 2018 Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect. PMID: 27002985 Mitsioni et al., 2016 103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were NOT found to be associated with nonsyndromic VUR or VUR-RHD. PMID: 24429398 Hwang et al., 2014 Cohort of 749 individuals from 650 different families with CAKUT, mostly from Eastern Europe (63%). 4 families had variants in ROBO2 - 2 of Indian origin, and 2 Eastern European. 4 unique ROBO2 missense variants were detected. Specific diagnoses of the 4 probands included Multicystic dysplastic kidney, Posterior urethral valves, Vesicoureteral reflux, and Ureteropelvic junction obstruction. ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026). |
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| Unexplained young onset end-stage renal disease - additional genes v2.6 | ROBO2 | Ida Ertmanska Classified gene: ROBO2 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.6 | ROBO2 | Ida Ertmanska Added comment: Comment on list classification: While there are more than 3 cases reported in literature with ROBO2 variants and vesicoureteral reflux, the evidence for this gene-disease association is limited and sometimes conflicting. Hence, this gene should remain Red. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.6 | ROBO2 | Ida Ertmanska Gene: robo2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.5 | ROBO2 | Ida Ertmanska Phenotypes for gene: ROBO2 were changed from Vesicoureteral reflux 2, OMIM:610878 to Vesicoureteral reflux 2, OMIM:610878; vesicoureteral reflux 2, MONDO:0012573 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.4 | ROBO2 | Ida Ertmanska Publications for gene: ROBO2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.3 | ROBO2 | Ida Ertmanska Mode of inheritance for gene: ROBO2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.73 | WDR4 | Ida Ertmanska Classified gene: WDR4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.73 | WDR4 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there are now 2 unrelated probands reported in literature with biallelic variants in WDR4 and early-onset seizures. Hence, this gene should be rated Amber, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.73 | WDR4 | Ida Ertmanska Gene: wdr4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.72 | WDR4 |
Luke Stuart changed review comment from: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation. Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity. Other reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347): PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy. PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy. PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy. Evidence linking WDR4 to an epilepsy/seizure phenotype (OMIM #618346, MIGSB) rests on a single publication (Shaheen et al. 2015, PMID 26416026) describing two patients from linked consanguineous families with one shared homozygous variant. An amber recommendation for early onset or syndromic epilepsy is recommended. Sources: Literature; to: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation. Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity. Other reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347): PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy. PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy. PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy. In summary, an epilepsy/seizure phenotype is described in two reports of WDR4-related disease, one comprising two patients from linked consanguineous families with one shared homozygous variant (Shaheen et al. 2015, PMID 26416026). An amber recommendation for early onset or syndromic epilepsy is recommended. Sources: Literature |
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| Early onset or syndromic epilepsy v9.72 | WDR4 |
Luke Stuart changed review comment from: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation. Subsequent reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347): PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy. PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy. PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy. Evidence linking WDR4 to an epilepsy/seizure phenotype (OMIM #618346, MIGSB) rests on a single publication (Shaheen et al. 2015, PMID 26416026) describing two patients from linked consanguineous families with one shared homozygous variant. An amber recommendation for early onset or syndromic epilepsy is recommended. Sources: Literature; to: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation. Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity. Other reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347): PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy. PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy. PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy. Evidence linking WDR4 to an epilepsy/seizure phenotype (OMIM #618346, MIGSB) rests on a single publication (Shaheen et al. 2015, PMID 26416026) describing two patients from linked consanguineous families with one shared homozygous variant. An amber recommendation for early onset or syndromic epilepsy is recommended. Sources: Literature |
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| Unexplained young onset end-stage renal disease - additional genes v2.2 | ROBO2 | Ida Ertmanska edited their review of gene: ROBO2: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.2 | ROBO2 | Ida Ertmanska edited their review of gene: ROBO2: Changed publications to: 27002985, 29194579, 32041992, 34059960 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.2 | ROBO2 |
Ida Ertmanska changed review comment from: PMID: 34059960 Liu et al., 2021 Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux. Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1) Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1) Both classified VUS in the paper according to ACMG criteria. PMID: 32041992 Darlow et al., 2020 Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants. Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2. PMID: 29194579 Rasmussen et al., 2018 Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect. ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026).; to: PMID: 34059960 Liu et al., 2021 Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux. Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1) Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1) Both classified VUS in the paper according to ACMG criteria. PMID: 32041992 Darlow et al., 2020 Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants. Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2. PMID: 29194579 Rasmussen et al., 2018 Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect. PMID: 27002985 Mitsioni et al., 2016 103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were NOT found to be associated with nonsyndromic VUR or VUR-RHD. ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026). |
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| Proteinuric renal disease v6.16 | WDR4 | Ida Ertmanska Phenotypes for gene: WDR4 were changed from growth deficiency; microcephaly; developmental delay; intellectual disability; proteinuria; nephrotic syndrome to Galloway-Mowat syndrome 6, OMIM:61834; Galloway-Mowat syndrome 6, MONDO:0032691 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.15 | WDR4 | Ida Ertmanska Classified gene: WDR4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.15 | WDR4 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart and John Sayer, there are now 2 unrelated probands reported in literature with biallelic variants in WDR4 and proteinuria. Hence, this gene should be rated Amber, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.15 | WDR4 | Ida Ertmanska Gene: wdr4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.7 | GLT8D1 | Achchuthan Shanmugasundram Classified gene: GLT8D1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.7 | GLT8D1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated amber despite having large number of cases and some functional data (zebrafish motor deficits, neuronal cell morphology changes, enzyme activity loss). This is because several reported variants were excluded from scoring due to population frequencies too high to be consistent with disease, gene-wide burden analysis shows no significant ALS association once the exon 4 cluster is excluded, and several cases with p.Arg92Cys variant also co-carrying ARPP21 variant. In addition, this gene is rated as 'Limited' in ClinGen for ALS phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.7 | GLT8D1 | Achchuthan Shanmugasundram Gene: glt8d1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.6 | GLT8D1 | Achchuthan Shanmugasundram Phenotypes for gene: GLT8D1 were changed from familial amyotrophic lateral sclerosis, MONDO:0005144 to amyotrophic lateral sclerosis, MONDO:0004976 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.5 | GLT8D1 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos. GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles. PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions. PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity. This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967).; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles. Burden analysis showed there is no significant ALS-association within GLT8D1 when exon 4 is excluded. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos. PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions. Burden analysis in sALS cohort showed that there is no significant enrichment of rare GLT8D1 variants versus gnomAD East Asian controls at either whole-gene level (4 variants/1,410 combined sALS cases vs 25 variants/9,766 gnomAD controls) or exon 4–specific level (0 variants in sALS vs 3 in controls). PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity. This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967). |
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| Early onset or syndromic epilepsy v9.72 | WDR4 |
Luke Stuart gene: WDR4 was added gene: WDR4 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: WDR4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WDR4 were set to 26416026; 28617965; 29597095; 30079490 Phenotypes for gene: WDR4 were set to Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618346; Galloway-Mowat syndrome 6, OMIM:618347 Review for gene: WDR4 was set to AMBER Added comment: PMID 26416026 (Shaheen et al., 2015): Two patients from presumed unrelated, but geographically linked, consanguineous Egyptian families were homozygous for WDR4 c.509G>T (p.Arg170Leu). Both presented with severe prenatal and postnatal growth restriction, severe microcephaly, profound developmental impairment, early-onset epilepsy (seizure onset at 10 months and 4 months), hypertonia/spasticity, optic atrophy, and distinctive facial dysmorphism. Functional studies demonstrated that the variant impairs WDR4 function, resulting in reduced tRNA m7G46 methylation. Subsequent reports of WDR4-related disease have not described epilepsy, reporting phenotypes consistent with Galloway-Mowat syndrome 6 (OMIM: 618347): PMID 28617965 (Trimouille et al., 2018): Two sisters with compound heterozygous WDR4 variants (c.509G>A; p.Arg170Gln and c.911_927dup; p.Gln310GlyfsTer30) presented with severe microcephaly, growth retardation, and severe intellectual disability, without seizures or epilepsy. PMID 29597095 (Chen et al., 2018): A patient with compound heterozygous WDR4 variants (c.491A>C; p.Asp164Ala and c.940dupC; p.Leu314ProfsTer16) had speech and language delay, without a history of seizures or epilepsy. PMID 30079490 (Braun et al., 2018): Four siblings homozygous for WDR4 c.454-2A>C presented with microcephaly, developmental delay, and, in most cases, nephrotic syndrome consistent with Galloway-Mowat syndrome; none had seizures or epilepsy. Evidence linking WDR4 to an epilepsy/seizure phenotype (OMIM #618346, MIGSB) rests on a single publication (Shaheen et al. 2015, PMID 26416026) describing two patients from linked consanguineous families with one shared homozygous variant. An amber recommendation for early onset or syndromic epilepsy is recommended. Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.5 | GLT8D1 |
Achchuthan Shanmugasundram changed review comment from: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos. GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles. PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions. PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity. This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen.; to: PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene. Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos. GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles. PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions. PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity. This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967). |
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| Neurodegenerative disorders, adult onset v9.5 | GLT8D1 | Achchuthan Shanmugasundram reviewed gene: GLT8D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30811981, 33581933, 34746377; Phenotypes: amyotrophic lateral sclerosis, MONDO:0004976; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.2 | ROBO2 | Ida Ertmanska reviewed gene: ROBO2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29194579, 32041992, 34059960; Phenotypes: Vesicoureteral reflux 2, OMIM:610878, vesicoureteral reflux 2, MONDO:0012573; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.7 | XPNPEP3 | Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated families reported in literature with biallelic XPNPEP3 variants and paediatric cardiomyopathy (1 from a pre-print article). Hence, this gene should remain Amber until more evidence emerges.; to: Comment on list classification: There are now 3 unrelated families reported in literature with biallelic XPNPEP3 variants and paediatric cardiomyopathy (1 from a pre-print article). Hence, this gene should remain Amber on Paediatric or syndromic cardiomyopathy until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.7 | XPNPEP3 | Ida Ertmanska Classified gene: XPNPEP3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.7 | XPNPEP3 | Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated families reported in literature with biallelic XPNPEP3 variants and paediatric cardiomyopathy (1 from a pre-print article). Hence, this gene should remain Amber until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.7 | XPNPEP3 | Ida Ertmanska Gene: xpnpep3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.6 | XPNPEP3 |
Ida Ertmanska gene: XPNPEP3 was added gene: XPNPEP3 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: XPNPEP3 were set to 20179356; 35328774; 39363162; doi:https://doi.org/10.1101/2025.01.11.25320052 Phenotypes for gene: XPNPEP3 were set to cardiomyopathy, MONDO:0004994 Review for gene: XPNPEP3 was set to AMBER Added comment: PMID: 20179356 O'Toole et al., 2010 2 affected individuals of kindred F543 (Turkish decent) had a homozygous 4-base deletion in XPNPEP3 c.931_934 delAACA, (p.N311LfsX5). Patient phenotype: Cardiomyopathy, seizure, mental/developmental delay, chronic pancreatitis with pancreatic cysts, mitochondrial disorder. Kindred A131 - 3 affected individuals (North Finnish) harboured a homozygous splice-site mutation (1357G>T) in XPNPEP3. Patient phenotype: mild form of an NPHP-like kidney disease, with residual kidney function beyond the age of 20 years; hypertension, essential tremor, hearing loss. PMID: 39363162 Zhen et al., 2024 13-year-old Chinese female patient with intellectual disability presented with a 2-year history of convulsions and fatigue, with a recent episode of swelling, breathlessness, and nocturnal dyspnea. The patient was diagnosed with cardiomyopathy, ventricular tachycardia, heart failure, and kidney failure. WES revealed a homozygous c.970–2A > G mutation in XPNPEP3. doi:https://doi.org/10.1101/2025.01.11.25320052 Ruijmbeek et al., 2025 - PRE-PRINT Report of two siblings with renal insufficiency and rapidly progressive cardiomyopathy revealed a novel homozygous variant (NM_022098.4 c.1357G>A) in the XPNPEP3 gene, showed to cause abnormal splicing, leading to an abnormal transcript and loss of XPNPEP3 protein function. PMID: 35328774 Wachoski-Dark et al., 2022 - review article XPNPEP3 is a mitochondrial protease that is responsible for the secondary cleavage of proteins localized to the matrix. XPNPEP3-related disease is caused by mitochondrial dysfunction rather than ciliary dysfunction (hypothesised previously). Sources: Literature |
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| Cutaneous photosensitivity with a likely genetic cause v3.18 | UROD | Luke Stuart reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: 40534320, 38813949, 9211196, 24175354, 23741761; Phenotypes: Porphyria cutanea tarda, OMIM:176100, Porphyria, hepatoerythropoietic, OMIM:176100, Familial porphyria cutanea tarda, MONDO:0008296, Hepatoerythropoietic porphyria, MONDO:0019799; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.1 | UROD | Luke Stuart reviewed gene: UROD: Rating: GREEN; Mode of pathogenicity: None; Publications: 6112327, 24175354, 39644053, 12735639, 11134514, 9806541; Phenotypes: Porphyria cutanea tarda, OMIM:176100, Porphyria, hepatoerythropoietic, OMIM:176100, Familial porphyria cutanea tarda, MONDO:0008296, Hepatoerythropoietic porphyria, MONDO:0019799; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.23 | GIGYF1 | Achchuthan Shanmugasundram Classified gene: GIGYF1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.23 | GIGYF1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene is identified with significant enrichment in multiple large cohorts of autism spectrum disorder patients. Detailed clinical information was only available for a small subset of patients, from which intellectual disability was reported in 11/25 patients. However, severity of ID was not provided for any of these patients. Hence, this gene is rated amber with 'watchlist' tag added. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.23 | GIGYF1 | Achchuthan Shanmugasundram Gene: gigyf1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.22 | GIGYF1 | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: GIGYF1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.22 | GIGYF1 | Achchuthan Shanmugasundram Phenotypes for gene: GIGYF1 were changed from Developmental disorder to autism spectrum disorder, MONDO:0005258; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.21 | GIGYF1 | Achchuthan Shanmugasundram Publications for gene: GIGYF1 were set to 33057194 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.20 | GIGYF1 | Achchuthan Shanmugasundram reviewed gene: GIGYF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 33057194, 35917186, 36924980; Phenotypes: autism spectrum disorder, MONDO:0005258, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.31 | COL6A3 |
Alexander Rossor gene: COL6A3 was added gene: COL6A3 was added to Hereditary neuropathy or pain disorder. Sources: Expert list Mode of inheritance for gene: COL6A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COL6A3 were set to 42520849 Phenotypes for gene: COL6A3 were set to motor neuropathy; myopathy Mode of pathogenicity for gene: COL6A3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: COL6A3 was set to GREEN Added comment: Case series of 35 patients showing evidence of both a peripheral motor neuropathy and myopathy Sources: Expert list |
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| Intellectual disability v11.20 | LDB1 | Achchuthan Shanmugasundram Phenotypes for gene: LDB1 were changed from Congenital hydrocephalus, MONDO:0016349 to neurodevelopmental disorder, MONDO:0700092; congenital hydrocephalus, MONDO:0016349 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.19 | LDB1 | Achchuthan Shanmugasundram Publications for gene: LDB1 were set to 39680505; 38091987; 33077954 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.18 | LDB1 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: LDB1 was changed from None to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.18 | LDB1 |
Achchuthan Shanmugasundram changed review comment from: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, distinguishing two variant classes with distinct phenotypic and mechanistic consequences. Ventriculomegaly/enlarged ventricles was observed in 9/9 individuals with detailed clinical data who carried C-terminal LID-disrupting (frameshift/nonsense/splice-site) variants, versus only 1/7 individuals with N-terminal LGD or DD-missense variants. Four C-terminal LID-disrupting LGD variants (p.Ser317Argfs21, p.Gln333, p.Glu349Serfs134, p.Arg356Serfs127) and one LID missense variant (p.Thr359Pro) were newly reported, in addition to prior literature reports of 8 C-terminal LGD + 1 missense variant. All these evidence support a genotype-specific association between C-terminal LDB1 variants and hydrocephalus/ventriculomegaly. C-terminal LID-affecting LDB1 variants abolished LHX2 binding and act dominant-negatively, suppressing wild-type LDB1–LHX2 interaction below expected levels while also showing increased protein stability and nuclear aggregate formation unlike N-terminal variants. This dominant-negative mechanism was also confirmed in vivo, as C-terminal variants worsened viability upon overexpression and failed to rescue (or exacerbated) chi loss-of-function phenotypes in Drosophila, in contrast to N-terminal variants.; to: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, distinguishing two variant classes with distinct phenotypic and mechanistic consequences. Ventriculomegaly/enlarged ventricles was observed in 9/9 individuals with detailed clinical data who carried C-terminal LID-disrupting (frameshift/nonsense/splice-site) variants, versus only 1/7 individuals with N-terminal LGD or DD-missense variants. Four C-terminal LID-disrupting LGD variants (p.Ser317Argfs21, p.Gln333, p.Glu349Serfs134, p.Arg356Serfs127) and one LID missense variant (p.Thr359Pro) were newly reported, in addition to prior literature reports of 8 C-terminal LGD + 1 missense variant. All these evidence support a genotype-specific association between C-terminal LDB1 variants and hydrocephalus/ventriculomegaly. C-terminal LID-affecting LDB1 variants abolished LHX2 binding and act dominant-negatively, suppressing wild-type LDB1–LHX2 interaction below expected levels while also showing increased protein stability and nuclear aggregate formation unlike N-terminal variants. This dominant-negative mechanism was also confirmed in vivo, as C-terminal variants worsened viability upon overexpression and failed to rescue (or exacerbated) chi loss-of-function phenotypes in Drosophila, in contrast to N-terminal variants. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 16 August 2026). |
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| Intellectual disability v11.17 | LDB1 |
Achchuthan Shanmugasundram changed review comment from: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, of which 14 patients presented with developmental delay, 13 patients with speech delay and 8 patients with motor delay. There were eight other patients reported previously. Developmental delay was present in 9/11 individuals with N-terminal LGD/DD missense variants and 7/7 individuals with C-terminal LID-affecting variants, speech delay present in 10/10 and 5/5, and motor delay present in 5/9 and 5/5 respectively. Unlike the ventriculomegaly phenotype, developmental delay occurs across both N-terminal and C-terminal variant classes, indicating it is a core, mechanism-independent feature of LDB1-related neurodevelopmental disorder. N-terminal DD missense variants impair LDB1 homodimerization through loss-of-function, while C-terminal LID variants abolish LHX2 binding via a dominant-negative mechanism, both disrupting transcriptional complexes required for neurogenesis. In Drosophila, neuronal knockdown of the LDB1 ortholog chi impaired motor behavior, and both variant types failed to properly rescue this phenotype, confirming LDB1 dysfunction causally contributes to neurological/developmental impairment. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; to: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, of which 14 patients presented with developmental delay, 13 patients with speech delay and 8 patients with motor delay. There were eight other patients reported previously. Developmental delay was present in 9/11 individuals with N-terminal LGD/DD missense variants and 7/7 individuals with C-terminal LID-affecting variants, speech delay present in 10/10 and 5/5, and motor delay present in 5/9 and 5/5 respectively. Unlike the ventriculomegaly phenotype, developmental delay occurs across both N-terminal and C-terminal variant classes, indicating it is a core, mechanism-independent feature of LDB1-related neurodevelopmental disorder. N-terminal DD missense variants impair LDB1 homodimerization through loss-of-function, while C-terminal LID variants abolish LHX2 binding via a dominant-negative mechanism, both disrupting transcriptional complexes required for neurogenesis. In Drosophila, neuronal knockdown of the LDB1 ortholog chi impaired motor behavior, and both variant types failed to properly rescue this phenotype, confirming LDB1 dysfunction causally contributes to neurological/developmental impairment. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 16 August 2026). |
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| Intellectual disability v11.17 | LDB1 | Achchuthan Shanmugasundram reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 42320471; Phenotypes: neurodevelopmental disorder, MONDO:0700092, congenital hydrocephalus, MONDO:0016349; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.18 | LDB1 | Achchuthan Shanmugasundram Phenotypes for gene: LDB1 were changed from Congenital hydrocephalus, MONDO:0016349 to congenital hydrocephalus, MONDO:0016349; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.17 | LDB1 | Achchuthan Shanmugasundram Publications for gene: LDB1 were set to 39680505; 38091987; 33077954 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.16 | LDB1 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: LDB1 was changed from None to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.15 | LDB1 | Achchuthan Shanmugasundram reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 42320471; Phenotypes: congenital hydrocephalus, MONDO:0016349, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.10 | ELOVL5 |
Ida Ertmanska changed review comment from: PMID: 40940404 Watanabe et al., 2025 Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done. PMID: 32314013 Gazulla et al., 2020 Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease. PMID: 25065913 DiGregorio et al., 2014 Three SCA-affected Italian families (2 have confirmed shared ancestry, third may be more distantly related or same variant arose spontaneously). ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Disease onset was around 34-45 years of age, with slowly progressive symptoms. Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. The female proband had ataxia with age of onset 51 years. FUNCTIONAL EVIDENCE: PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913 Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%. ; to: PMID: 40940404 Watanabe et al., 2025 Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done. PMID: 32314013 Gazulla et al., 2020 Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease. PMID: 25065913 DiGregorio et al., 2014 Three SCA-affected Italian families (2 have confirmed shared ancestry, third may be more distantly related or same variant arose spontaneously). ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Disease onset was around 34-45 years of age, with slowly progressive symptoms. Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. The female proband had ataxia with age of onset 51 years. FUNCTIONAL EVIDENCE: PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913 Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%. This gene is associated with AD Spinocerebellar ataxia 38, MIM:615957 (OMIM accessed 14th Aug 2026). |
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| Hereditary ataxia, adult onset v9.10 | ELOVL5 | Ida Ertmanska Phenotypes for gene: ELOVL5 were changed from Spinocerebellar ataxia 38, 615957; Spinocerebellar ataxia 36 615957 to Spinocerebellar ataxia 38, OMIM:615957; spinocerebellar ataxia type 38, MONDO:0014417 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.9 | ELOVL5 | Ida Ertmanska Publications for gene: ELOVL5 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.8 | ELOVL5 | Ida Ertmanska Mode of inheritance for gene: ELOVL5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.7 | ELOVL5 | Ida Ertmanska Mode of pathogenicity for gene: ELOVL5 was changed from Other - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.6 | ELOVL5 | Ida Ertmanska Classified gene: ELOVL5 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.6 | ELOVL5 | Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated families reported in literature with 3 unique monoallelic ELOVL5 missense variants, affected by adult-onset spinocerebellar ataxia. There is also a fourth pedigree, reported in PMID: 32314013, with a likely benign variant with a high allele frequency in gnomAD (not counted). Based on available evidence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.6 | ELOVL5 | Ida Ertmanska Gene: elovl5 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.5 | ELOVL5 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ELOVL5. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.5 | ELOVL5 |
Ida Ertmanska changed review comment from: PMID: 40940404 Watanabe et al., 2025 Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done. PMID: 32314013 Gazulla et al., 2020 Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease. PMID: 25065913 DiGregorio et al., 2014 SCA-affected Italian family. ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. FUNCTIONAL EVIDENCE: PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913 Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.; to: PMID: 40940404 Watanabe et al., 2025 Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done. PMID: 32314013 Gazulla et al., 2020 Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease. PMID: 25065913 DiGregorio et al., 2014 Three SCA-affected Italian families (2 have confirmed shared ancestry, third may be more distantly related or same variant arose spontaneously). ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Disease onset was around 34-45 years of age, with slowly progressive symptoms. Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. The female proband had ataxia with age of onset 51 years. FUNCTIONAL EVIDENCE: PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913 Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%. |
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| Hereditary ataxia, adult onset v9.5 | ELOVL5 |
Ida Ertmanska changed review comment from: PMID: 40940404 Watanabe et al., 2025 Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done. PMID: 32314013 Gazulla et al., 2020 Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote. PMID: 25065913 DiGregorio et al., 2014 SCA-affected Italian family. ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. FUNCTIONAL EVIDENCE: PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913 Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.; to: PMID: 40940404 Watanabe et al., 2025 Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done. PMID: 32314013 Gazulla et al., 2020 Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease. PMID: 25065913 DiGregorio et al., 2014 SCA-affected Italian family. ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. FUNCTIONAL EVIDENCE: PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913 Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%. |
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| Hereditary ataxia, adult onset v9.5 | ELOVL5 | Ida Ertmanska edited their review of gene: ELOVL5: Changed publications to: 25065913, 32314013, 37199746, 40940404 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.5 | ELOVL5 |
Ida Ertmanska changed review comment from: PMID: 40940404 Watanabe et al., 2025 Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected.; to: PMID: 40940404 Watanabe et al., 2025 Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done. PMID: 32314013 Gazulla et al., 2020 Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote. PMID: 25065913 DiGregorio et al., 2014 SCA-affected Italian family. ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. FUNCTIONAL EVIDENCE: PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913 Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%. |
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| Proteinuric renal disease v6.14 | WDR4 |
Luke Stuart changed review comment from: Renal features including proteinuria and nephrotic syndrome have been noted in a subset of Galloway Mowat Syndrome 6 (GAMOS6) patients: Braun et al., 2018 (PMID 30079490): A GAMOS family was investigated via WES. WDR4 c.454-2A>C (homozygous) segregated with disease in four siblings, three of whom demonstrated renal involvement (nephrotic range proteinuria). Severity was variable; only one child (B1028-21) developed overt nephrotic syndrome including edema and hypalbuminemia. Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity. At 5 years, the patient developed occasional mild proteinuria (1+) with no associated symptoms, progressing to hypoalbuminemia (2.5 mg/dL), proteinuria (3+) and increased urine protein-to-creatinine ratio (3.0) at 6 years. Nephrotic syndrome was diagnosed. Emerging evidence suggests renal abnormalities as a component of the GAMOS6 phenotype. An amber classification is recommended based on the observation of four individuals from two independent families presenting with proteinuria, two of whom developed overt nephrotic syndrome. Characterisation of additional WDR4-related GAMOS patients is necessary to establish a clear relationship. WDR4 is associated with Galloway-Mowat syndrome 6 (OMIM #61834) and Microcephaly, growth deficiency, seizures, and brain malformations (OMIM #618346), accessed 08/2026.; to: WDR4 is associated with Galloway-Mowat syndrome 6 (OMIM #61834) and Microcephaly, growth deficiency, seizures, and brain malformations (OMIM #618346), accessed 08/2026. Renal features including proteinuria and nephrotic syndrome have been noted in a subset of Galloway Mowat Syndrome 6 (GAMOS6) patients: Braun et al., 2018 (PMID 30079490): A GAMOS family was investigated via WES. WDR4 c.454-2A>C (homozygous) segregated with disease in four siblings, three of whom demonstrated renal involvement (nephrotic range proteinuria). Severity was variable; only one child (B1028-21) developed overt nephrotic syndrome including edema and hypalbuminemia. Kim et al., 2020 (Case report, journal of Genetic Medicine, 10.5734/jgm.2020.17.2.97): Trio WES identified compound heterozygous WDR4 variants (c.540C>G (p.Ile180Met) and c.494G>A (p.Arg165Gln)) in a patient presenting with seizure, delayed development, and microcephaly at referral. Both variants were classified VUS- rare in Gnomad v4 (0 homozygotes) with equivocal REVEL scores favouring benignity. At 5 years, the patient developed occasional mild proteinuria (1+) with no associated symptoms, progressing to hypoalbuminemia (2.5 mg/dL), proteinuria (3+) and increased urine protein-to-creatinine ratio (3.0) at 6 years. Nephrotic syndrome was diagnosed. Emerging evidence suggests renal abnormalities as a component of the GAMOS6 phenotype. An amber classification is recommended based on the observation of four individuals from two independent families presenting with proteinuria, two of whom developed overt nephrotic syndrome. Characterisation of additional WDR4-related GAMOS patients is necessary to establish a clear relationship. |
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| Proteinuric renal disease v6.14 | WDR4 | Luke Stuart reviewed gene: WDR4: Rating: AMBER; Mode of pathogenicity: None; Publications: 30079490; Phenotypes: Galloway-Mowat syndrome 6, OMIM:61834, Galloway-Mowat syndrome 6, MONDO:0032691; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.5 | ELOVL5 | Ida Ertmanska reviewed gene: ELOVL5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40940404; Phenotypes: Spinocerebellar ataxia 38, OMIM:615957, spinocerebellar ataxia type 38, MONDO:0014417; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.30 | GPN2 | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Luke Stuart, there are now 2 pedigrees reported where individuals harbouring biallelic GPN2 variants presented with ataxia (2 sibs, age of onset not specified), and cerebellar atrophy (both families). Based on available evidence, this gene can only be rated Amber.; to: Comment on list classification: As reviewed by Luke Stuart, there are now 2 pedigrees reported where individuals harbouring biallelic GPN2 variants presented with ataxia (2 sibs, age of onset not specified), and cerebellar atrophy (both families). These families were found to have shared ancestry - counted as 1 family. Based on available evidence, this gene can only be rated Red. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.30 | GPN2 | Ida Ertmanska Tag founder-effect tag was added to gene: GPN2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.30 | GPN2 | Ida Ertmanska Classified gene: GPN2 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.30 | GPN2 | Ida Ertmanska Gene: gpn2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.5 | LONP1 | Ida Ertmanska Phenotypes for gene: LONP1 were changed from CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.4 | LONP1 | Ida Ertmanska Phenotypes for gene: LONP1 were changed from CODAS (Cerebral, Ocular, Dental, Auricular and Skeletal anomalies) syndrome 600373 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.26 | CDK6 | Ida Ertmanska Tag watchlist tag was added to gene: CDK6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.26 | CDK6 | Ida Ertmanska Publications for gene: CDK6 were set to 25951892; 25548773; 23918663 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.25 | CDK6 | Ida Ertmanska Phenotypes for gene: CDK6 were changed from Autosomal recessive primary microcephaly (MCPH) ; ?Microcephaly 12, primary, autosomal recessive, 616080 to ?Microcephaly 12, primary, autosomal recessive, OMIM:616080; microcephaly 12, primary, autosomal recessive, MONDO:0014484 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.24 | CDK6 | Ida Ertmanska Classified gene: CDK6 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.24 | CDK6 | Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported in literature with biallelic CDK6 variants and severe microcephaly (more than 3SD below average). Hence, this gene can be rated Amber with current evidence. A 'watchlist' tag was added in anticipation of further reports. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.24 | CDK6 | Ida Ertmanska Gene: cdk6 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.3 | LONP1 | Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.23 | CDK6 | Ida Ertmanska edited their review of gene: CDK6: Changed publications to: 23918663, 41856556 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.23 | CDK6 |
Ida Ertmanska changed review comment from: PMID: 41856556 Isik et al., 2026 Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous. Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.; to: PMID: 41856556 Isik et al., 2026 Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous. Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI. Individuals in PMID:23918663 (see review by Rebecca Foulger) had severe microcephaly of -4 SD and -6SD. |
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| Severe microcephaly v9.23 | CDK6 |
Ida Ertmanska changed review comment from: PMID: 41856556 Isik et al., 2026 Report of a female child (Case 3) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.; to: PMID: 41856556 Isik et al., 2026 Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous. Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI. |
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| Severe microcephaly v9.23 | CDK6 | Ida Ertmanska reviewed gene: CDK6: Rating: AMBER; Mode of pathogenicity: None; Publications: 41856556; Phenotypes: ?Microcephaly 12, primary, autosomal recessive, OMIM:616080, microcephaly 12, primary, autosomal recessive, MONDO:0014484; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pyruvate dehydrogenase (PDH) deficiency v1.44 | LONP1 | Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS syndrome OMIM:600373; CODAS syndrome MONDO:0010879 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pyruvate dehydrogenase (PDH) deficiency v1.43 | LONP1 | Achchuthan Shanmugasundram Publications for gene: LONP1 were set to 30304514 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.11 | LONP1 | Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS syndrome, 600373 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.10 | LONP1 | Achchuthan Shanmugasundram Publications for gene: LONP1 were set to 25574826; 26622071; 27878435; 29408517; 25808063; 28148925 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pyruvate dehydrogenase (PDH) deficiency v1.42 | LONP1 | Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska changed review comment from: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including optic atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation, though optic atrophy is not specifically mentioned. Hence, this gene can only be rated Amber on Optic neuropathy with the current evidence.; to: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including optic atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation, though optic atrophy is not specifically mentioned. Hence, this gene can only be rated Amber on Optic neuropathy with the current evidence. It was tagged for promotion to Green on Paediatric disorders - additional genes, to ensure inclusion on R27. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.23 | ZNHIT3 | Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.23 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.23 | ZNHIT3 | Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including microcephaly. However, the severity is not stated in PMID: 28335020. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation with microcephaly. Hence, this gene can only be rated Amber with the current evidence. It was tagged for promotion to Green on Paediatric disorders - additional genes, to ensure inclusion on R27. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.23 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.4 | ZNHIT3 | Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.13 | ZNHIT3 | Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.13 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.13 | ZNHIT3 | Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including childhood-onset cerebellar atrophy, optic atrophy, oedema, microcephaly, infantile spasms, and profound developmental delay. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation similar to reported patients. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.13 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.9 | LONP1 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are >3 patients reported with biallelic variants and congenital cataracts. However, only one patient with monoallelic variant presented with cataracts. Hence, the MOI should remain as BIALLELIC. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.9 | LONP1 | Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.29 | ZNHIT3 | Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.8 | LONP1 | Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.29 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.29 | ZNHIT3 | Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including childhood-onset cerebellar atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation with structural cerebellar anomalies. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.29 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska Tag founder-effect tag was added to gene: ZNHIT3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including optic atrophy. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation, though optic atrophy is not specifically mentioned. Hence, this gene can only be rated Amber on Optic neuropathy with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.51 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.7 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.7 | ZNHIT3 | Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including oedema. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation with pericardiac oedema. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.7 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.6 | ZNHIT3 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ZNHIT3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.50 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.12 | ZNHIT3 |
Ida Ertmanska gene: ZNHIT3 was added gene: ZNHIT3 was added to Paediatric disorders - additional genes. Sources: Literature Q3_26_promote_green tags were added to gene: ZNHIT3. Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNHIT3 were set to 28335020; 31048081; 39252897; 40178020 Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841 Review for gene: ZNHIT3 was set to GREEN Added comment: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each. She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Brain MRI showed cerebral, cerebellar and brainstem atrophy and thin corpus callosum. Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. PMID: 28335020 Anttonen et al., 2017 Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features. All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported. Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability. Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant. FUNCTIONAL EVIDENCE: PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development. Sources: Literature |
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| Severe microcephaly v9.22 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.28 | ZNHIT3 |
Ida Ertmanska gene: ZNHIT3 was added gene: ZNHIT3 was added to Ataxia and cerebellar anomalies - childhood onset. Sources: Literature Q3_26_promote_green tags were added to gene: ZNHIT3. Mode of inheritance for gene: ZNHIT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNHIT3 were set to 28335020; 31048081; 39252897; 40178020 Phenotypes for gene: ZNHIT3 were set to PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841 Review for gene: ZNHIT3 was set to GREEN Added comment: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each. She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Brain MRI showed cerebral, cerebellar and brainstem atrophy and thin corpus callosum. Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. PMID: 28335020 Anttonen et al., 2017 Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features. All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported. Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability. Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant. FUNCTIONAL EVIDENCE: PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development. Sources: Literature |
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| Severe microcephaly v9.22 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.22 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.6 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.6 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.21 | ZNHIT3 |
Ida Ertmanska changed review comment from: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each. She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. PMID: 28335020 Anttonen et al., 2017 Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features. All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported. Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability. Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant. FUNCTIONAL EVIDENCE: PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each. She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Brain MRI showed cerebral, cerebellar and brainstem atrophy and thin corpus callosum. Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. PMID: 28335020 Anttonen et al., 2017 Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features. All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported. Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability. Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant. FUNCTIONAL EVIDENCE: PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development. |
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| Primary lymphoedema v5.5 | ZNHIT3 | Ida Ertmanska Phenotypes for gene: ZNHIT3 were changed from PEHO syndrome, 260565 to PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.4 | ZNHIT3 | Ida Ertmanska Publications for gene: ZNHIT3 were set to 28335020 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.3 | ZNHIT3 | Ida Ertmanska reviewed gene: ZNHIT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28335020, 31048081, 39252897, 40178020; Phenotypes: PEHO syndrome, OMIM:260565, PEHO syndrome, MONDO:0009841; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.21 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: GREEN; Changed publications to: 28335020, 31048081, 39252897, 40178020; Changed phenotypes to: PEHO syndrome, OMIM:260565, PEHO syndrome, MONDO:0009841; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.21 | ZNHIT3 | Ida Ertmanska commented on gene: ZNHIT3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.21 | ZNHIT3 | Ida Ertmanska Publications for gene: ZNHIT3 were set to 28335020 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.20 | ZNHIT3 | Ida Ertmanska Phenotypes for gene: ZNHIT3 were changed from PEHO syndrome, 260565; microcephaly to Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.50 | ZNHIT3 | Ida Ertmanska Phenotypes for gene: ZNHIT3 were changed from Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) 260565 to Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.49 | ZNHIT3 | Ida Ertmanska Publications for gene: ZNHIT3 were set to 28335020 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.48 | ZNHIT3 | Ida Ertmanska Classified gene: ZNHIT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.48 | ZNHIT3 | Ida Ertmanska Gene: znhit3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 |
Ida Ertmanska changed review comment from: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each. She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. PMID: 28335020 Anttonen et al., 2017 Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features. All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported. Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability. Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant. FUNCTIONAL EVIDENCE: PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each. She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. PMID: 28335020 Anttonen et al., 2017 Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features. All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported. Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability. Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant. FUNCTIONAL EVIDENCE: PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development. |
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| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed publications to: 28335020, 31048081, 39252897, 40178020 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.27 | GPN2 | Achchuthan Shanmugasundram Phenotypes for gene: GPN2 were changed from Cerebellar ataxia (MONDO:0000437) to Cerebellar ataxia, MONDO:0000437 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 |
Ida Ertmanska changed review comment from: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each. She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each. She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. PMID: 28335020 Anttonen et al., 2017 Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features. All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported. Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability. Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant. FUNCTIONAL EVIDENCE: PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development. |
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| Intellectual disability v11.17 | GPN2 | Achchuthan Shanmugasundram Phenotypes for gene: GPN2 were changed from Intellectual disability (MONDO:0001071) to Intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.42 | GPN2 | Achchuthan Shanmugasundram Phenotypes for gene: GPN2 were changed from Sensorineural hearing loss disorder (MONDO:0020678) to Sensorineural hearing loss disorder, MONDO:0020678 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.5 | OGDH |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also some functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects. Hence, this gene can be rated amber with 'watchlist' tag added to review gene rating in light of any new evidence.; to: Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects. Hence, this gene can be rated green in the next GMS update. |
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| Hereditary ataxia, adult onset v9.5 | OGDH |
Achchuthan Shanmugasundram Tag watchlist was removed from gene: OGDH. Tag Q3_26_NHS_review tag was added to gene: OGDH. Tag Q3_26_promote_green tag was added to gene: OGDH. |
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| Hereditary ataxia, adult onset v9.5 | OGDH | Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.8 | COPB1 | Achchuthan Shanmugasundram Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly to Baralle-Macken syndrome, OMIM:619255; Baralle-Macken syndrome, MONDO:0031002 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.19 | COPB1 | Achchuthan Shanmugasundram Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly to Baralle-Macken syndrome, OMIM:619255; Baralle-Macken syndrome, MONDO:0031002 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.16 | COPB1 | Achchuthan Shanmugasundram Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly to Baralle-Macken syndrome, OMIM:619255; Baralle-Macken syndrome, MONDO:0031002 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.72 | DHX16 | Achchuthan Shanmugasundram Phenotypes for gene: DHX16 were changed from Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.15 | COPB1 |
Luke Stuart changed review comment from: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). All six patients had severe intellectual disability. In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability. Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 variant, c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts. A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.; to: COPB1 is associated with Baralle-Macken syndrome, OMIM:619255 (accessed 08/ 2026) Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). All six patients had severe intellectual disability. In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability. Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 variant, c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts. A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts. |
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| Intellectual disability v11.15 | COPB1 | Luke Stuart edited their review of gene: COPB1: Changed phenotypes to: Baralle-Macken syndrome, OMIM:619255, Baralle-Macken syndrome, MONDO:0031002 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.18 | COPB1 | Luke Stuart edited their review of gene: COPB1: Changed phenotypes to: Baralle-Macken syndrome, OMIM:619255, Baralle-Macken syndrome, MONDO:0031002 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.18 | COPB1 |
Luke Stuart changed review comment from: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability. Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts. A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.; to: COPB1 is associated with Baralle-Macken syndrome, OMIM:619255 (accessed 08/2026). Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability. Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts. A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts. |
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| Bilateral congenital or childhood onset cataracts v8.7 | COPB1 |
Luke Stuart changed review comment from: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability. Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts. All eight paediatric patients reported to date had severe early-onset cataracts (Khalid et al., 2025 (PMID 40396222); Macken et al., 2021 (PMID 33632302). A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.; to: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability. Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts. All eight paediatric patients reported to date had severe early-onset cataracts (Khalid et al., 2025 (PMID 40396222); Macken et al., 2021 (PMID 33632302). COPB1 is associated with Baralle-Macken syndrome, OMIM:619255 (accessed 08/2026). A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts. |
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| Bilateral congenital or childhood onset cataracts v8.7 | COPB1 | Luke Stuart edited their review of gene: COPB1: Changed phenotypes to: Baralle-Macken syndrome, OMIM:619255, Baralle-Macken syndrome, MONDO:0031002 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.71 | DHX16 | Ida Ertmanska Phenotypes for gene: DHX16 were changed from Neuromuscular disease and ocular or auditory anomalies with or without seizures 618733 to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.70 | DHX16 | Ida Ertmanska edited their review of gene: DHX16: Changed phenotypes to: Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.70 | DHX16 | Achchuthan Shanmugasundram Publications for gene: DHX16 were set to 31256877 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.69 | DHX16 | Achchuthan Shanmugasundram Mode of inheritance for gene: DHX16 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.15 | PDCD6IP | Achchuthan Shanmugasundram Phenotypes for gene: PDCD6IP were changed from microcephaly; Intellectual disability to ?Microcephaly 29, primary, autosomal recessive, OMIM:620047; microcephaly 29, primary, autosomal recessive, MONDO:0031060 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.14 | PDCD6IP | Achchuthan Shanmugasundram Publications for gene: PDCD6IP were set to 32286682 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.20 | NFATC2 | Achchuthan Shanmugasundram Classified gene: NFATC2 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.20 | NFATC2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one patient reported with biallelic NFATC2 variants and with joint contractures. Hence, this gene should be rated red with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.20 | NFATC2 | Achchuthan Shanmugasundram Gene: nfatc2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.19 | NFATC2 | Achchuthan Shanmugasundram Phenotypes for gene: NFATC2 were changed from ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369; lymphoproliferative syndrome, MONDO:0016537 to ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.18 | NFATC2 | Achchuthan Shanmugasundram Tag watchlist was removed from gene: NFATC2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.18 | NFATC2 |
Achchuthan Shanmugasundram changed review comment from: PMID:35789258 (2022) reported the first patient with complete NFAT1 (NFATC2) deficiency identified with a homozygous frameshift variant (c.2023_2026delTACC; p.Tyr675Thrfs*18). The patient presented with presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma, and immune profile showed accumulation of naïve B cells with oncogenic signatures (MYC, JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, aberrant CD8+ T cells. PMID:38427060 (2024) reported a 12-year-old female patient identified with a homozygous 6bp in-frame deletion (c.340_345delGAGATC; p.Glu114_Ile115del) and presenting with EBV-associated lymphoproliferation without skeletal involvement. This patient had recurrent chest infections, chronic wet cough, failure to thrive, generalised lymphadenopathy and severe hypogammaglobulinemia. The father and the healthy brother of the patient were heterozygous for the variant. As reviewed by Boaz Palterer, Bustamante-Ogando et al (2025) reported in a conference abstract (NOT a peer-reviewed manuscript) of a 12-year-old female patient with a severe, early-onset immunodeficiency characterised by recurrent sinopulmonary infections, bloody diarrhoea, chronic lung disease, and profound failure to thrive. Immunological analysis revealed anaemia and thrombocytosis, as well as pan-hypogammaglobulinemia, with reduced CD4+ and CD8+ T cells. Whole exome sequencing identified two novel, ultra-rare, highly conserved compound heterozygous missense variants in NFATC2 (p.Gly408Arg & p.Arg646Gln). This gene has been provisionally associated with MIM #620232 in OMIM (last accessed 11 August 2024).; to: PMID:35789258 (2022) reported the first patient with complete NFAT1 (NFATC2) deficiency identified with a homozygous frameshift variant (c.2023_2026delTACC; p.Tyr675Thrfs*18). The patient presented with presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma, and immune profile showed accumulation of naïve B cells with oncogenic signatures (MYC, JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, aberrant CD8+ T cells. PMID:38427060 (2024) reported a 12-year-old female patient identified with a homozygous 6bp in-frame deletion (c.340_345delGAGATC; p.Glu114_Ile115del) and presenting with EBV-associated lymphoproliferation without skeletal involvement. This patient had recurrent chest infections, chronic wet cough, failure to thrive, generalised lymphadenopathy and severe hypogammaglobulinemia. The father and the healthy brother of the patient were heterozygous for the variant. As reviewed by Boaz Palterer, Bustamante-Ogando et al (2025) reported in a conference abstract (NOT a peer-reviewed manuscript) of a 12-year-old female patient with a severe, early-onset immunodeficiency characterised by recurrent sinopulmonary infections, bloody diarrhoea, chronic lung disease, and profound failure to thrive. Immunological analysis revealed anaemia and thrombocytosis, as well as pan-hypogammaglobulinemia, with reduced CD4+ and CD8+ T cells. Whole exome sequencing identified two novel, ultra-rare, highly conserved compound heterozygous missense variants in NFATC2 (p.Gly408Arg & p.Arg646Gln). This gene has been provisionally associated with MIM #620232 in OMIM (last accessed 11 August 2024). |
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| Arthrogryposis v10.18 | NFATC2 | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.18 | NFATC2 | Achchuthan Shanmugasundram edited their review of gene: NFATC2: Changed rating: RED; Changed phenotypes to: ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232, joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.18 | NFATC2 | Achchuthan Shanmugasundram Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.18 | NFATC2 |
Achchuthan Shanmugasundram gene: NFATC2 was added gene: NFATC2 was added to Arthrogryposis. Sources: Expert Review Amber,Literature watchlist tags were added to gene: NFATC2. Mode of inheritance for gene: NFATC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NFATC2 were set to 35789258; 38427060 Phenotypes for gene: NFATC2 were set to ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369; lymphoproliferative syndrome, MONDO:0016537 Penetrance for gene: NFATC2 were set to unknown |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 | NFATC2 |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are only two unrelated cases published with biallelic NFATC2 variants and with a relevant phenotype. They displayed phenotypic variability with both displaying lymphoproliferative disorder, but only one with skeletal phenotype. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are only two unrelated cases published with biallelic NFATC2 variants and with a relevant phenotype. They displayed phenotypic variability with both displaying lymphoproliferative disorder, but only one with skeletal phenotype. Hence, this gene should be rated amber with the current evidence. The 'watchlist' tag has been added as there is an additional patient reported in a conference abstract with relevant phenotype. Hence, this gene should be reviewed and updated when additional published evidence become available. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 | NFATC2 | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: NFATC2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.4 | PCLO | Achchuthan Shanmugasundram Phenotypes for gene: PCLO were changed from Pontocerebellar hypoplasia, type 3, OMIM:608027 to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed phenotypes to: PEHO syndrome, OMIM:260565, PEHO syndrome, MONDO:0009841 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska edited their review of gene: ZNHIT3: Changed publications to: 31048081, 39252897 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 |
Ida Ertmanska changed review comment from: PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each. She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants. PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each. She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. |
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| Intellectual disability v11.13 | PCLO | Achchuthan Shanmugasundram Publications for gene: PCLO were set to 25832664 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.12 | PCLO | Achchuthan Shanmugasundram Phenotypes for gene: PCLO were changed from Pontocerebellar hypoplasia, type 3 to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | ZNHIT3 |
Ida Ertmanska changed review comment from: PMID: 31048081 Õunap et al., 2019 Report of a female patient (non-Finnish) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each. She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.; to: PMID: 31048081 Õunap et al., 2019 Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Unaffected parents het for a variant each. She had progressive microcephaly: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs. |
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| Optic neuropathy v6.47 | ZNHIT3 | Ida Ertmanska reviewed gene: ZNHIT3: Rating: AMBER; Mode of pathogenicity: None; Publications: 31048081; Phenotypes: PEHO syndrome, OMIM:260565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.11 | VWA8 | Ida Ertmanska Classified gene: VWA8 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.11 | VWA8 | Ida Ertmanska Added comment: Comment on list classification: There is one family reported in literature with a biallelic missense variant in VWA8 segregating with a complex neurodevelopmental disorder (PMID: 34660594). Other reports describe individuals with retinitis pigmentosa and monoallelic nonsense variants. Hence, this gene can only be rated Red on Intellectual disability with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.11 | VWA8 | Ida Ertmanska Gene: vwa8 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.10 | VWA8 |
Ida Ertmanska gene: VWA8 was added gene: VWA8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: VWA8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VWA8 were set to 34660594; 37012052; 40638000; 42120427 Phenotypes for gene: VWA8 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: VWA8 was set to RED Added comment: PMID: 40638000 Chacon-Camacho et al., 2025 Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1. PMID: 37012052 Kong et al., 2023 A single family with 11 individuals all presenting initial symptoms of visual defects which later progressed to macular changes, including macular degeneration and dystrophy. Two variants (c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter)) on the same allele of the VWA8 gene were found to segregate with disease. Expression studies showed reduced protein expression. Zebrafish knockdown model displayed a similar phenotype to that of humans. PMID: 34660594 Umair et al., 2021 Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs. Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish. PMID: 42120427 Kong et al., 2026 - Functional evidence - same research group as first patient report in PMID: 37012052 Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice. The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation. Sources: Literature |
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| Retinal disorders v9.19 | VWA8 | Ida Ertmanska commented on gene: VWA8: Comment on list classification: There are now 2 unrelated probands reported in literature with monoallelic nonsense variants in VWA8 and retinitis pigmentosa. A mouse model presented in PMID: 42120427 (Kong et al., 2026) is supportive of this disease association. Homozygous knockout mice had a more severe retinal phenotype than heterozygous mutants (though biallelic cases not yet reported in human). There is one pedigree reported with a bialellic VWA8 missense variant segregating with a complex neurodevelopmental disorder without retinal disease - potentially resulting from a different disease mechanism. Based on available evidence, this gene can be promoted to Green on Retinal disorders with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.19 | VWA8 | Ida Ertmanska Phenotypes for gene: VWA8 were changed from ?Retinitis pigmentosa 97, OMIM:620422 to ?Retinitis pigmentosa 97, OMIM:620422; retinitis pigmentosa 97, MONDO:0957314 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.18 | VWA8 | Ida Ertmanska Publications for gene: VWA8 were set to 37012052 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.17 | VWA8 |
Ida Ertmanska Tag watchlist was removed from gene: VWA8. Tag Q3_26_promote_green tag was added to gene: VWA8. |
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| Retinal disorders v9.17 | VWA8 |
Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025 Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1. PMID: 34660594 Umair et al., 2021 Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs. Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish PMID: 42120427 Kong et al., 2026 - Functional evidence Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice. The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation.; to: PMID: 40638000 Chacon-Camacho et al., 2025 Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1. PMID: 34660594 Umair et al., 2021 Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs. Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish PMID: 42120427 Kong et al., 2026 - Functional evidence - same research group as first patient report in PMID: 37012052 Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice. The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation. |
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| Retinal disorders v9.17 | VWA8 | Ida Ertmanska edited their review of gene: VWA8: Changed publications to: 34660594, 40638000, 42120427 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.17 | VWA8 |
Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025 Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1. PMID: 34660594 Umair et al., 2021 Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs. Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish.; to: PMID: 40638000 Chacon-Camacho et al., 2025 Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1. PMID: 34660594 Umair et al., 2021 Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs. Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish PMID: 42120427 Kong et al., 2026 - Functional evidence Authors constructed CRISPR Cas9 gene knockout mice with Vwa8 and identified Vwa8 wild-type, heterozygous (Vwa8+/-), and homozygous (Vwa8-/-) mice. Compared to the wild-type mice, the expression of the Hexokinase 2 (HK2) and Pyruvate kinase muscle (PKM) mitochondrial enzymes was reduced in mitochondria isolated from the retinal tissue of the Vwa8+/- and Vwa8-/- mice. The Vwa8+/- mice showed partial retina pigmentation compared to the wild-type mice, whereas the Vwa8-/- mice had more significant abnormal pigmentation of the fundus. Electroretinogram (ERG) analysis revealed a significant reduction in b-wave amplitudes under photopic conditions in 10-month-old Vwa8+/- mice when compared to wild-type controls, while it was more severe in Vwa8-/- mice with only minimal electrical responses to light stimulation. |
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| Autoinflammatory disorders v3.21 | PSMB8 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: PSMB8 was changed from to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.20 | PSMB8 | Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed mode of pathogenicity: Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.17 | VWA8 | Ida Ertmanska edited their review of gene: VWA8: Changed publications to: 34660594, 40638000 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.17 | VWA8 |
Ida Ertmanska changed review comment from: PMID: 40638000 Chacon-Camacho et al., 2025 Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1.; to: PMID: 40638000 Chacon-Camacho et al., 2025 Report of a Mexican patient suffering from retinitis pigmentosa. Classical features of retinal dystrophy were identified, including nyctalopia, peripheral visual field loss, as well as vascular attenuation, and bone spicules on fundus examination. Genetic analysis identified a novel pathogenic c.3069C>G (p.Tyr1023Ter) heterozygous VWA8 variant - 2 hets reported in gnomAD v4.1.1. PMID: 34660594 Umair et al., 2021 Report of a large consanguineous family of Saudi origin with a complex developmental syndrome: global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations. Affected individuals were homozygous for the VWA8: c.947A>G; p.(Asp316Gly) variant - reported in 29 het individuals in gnomAD v4.1.1 (no homozygotes). Seq method: WES + Sanger confirmation in the parents and sibs. Functional evidence: zebrafish morpholino approach showed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism in vwa8-knockdown fish. |
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| Retinal disorders v9.17 | VWA8 | Ida Ertmanska reviewed gene: VWA8: Rating: GREEN; Mode of pathogenicity: None; Publications: 40638000; Phenotypes: ?Retinitis pigmentosa 97, OMIM:620422, retinitis pigmentosa 97, MONDO:0957314; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.68 | SEC31A | Ida Ertmanska Tag watchlist was removed from gene: SEC31A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.3 | SEC31A | Ida Ertmanska Classified gene: SEC31A as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.3 | SEC31A | Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated probands reported with 3 unique homozygous variants in SEC31A and a highly syndromic presentation, resulting in early lethality. Two individuals had IUGR. In addition, a neuron-specific sec31a knock-down in Drosophila recapitulated early lethality seen in the patients. Based on available evidence, this gene should be Green on Fetal anomalies. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.3 | SEC31A | Ida Ertmanska Gene: sec31a has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.11 | SEC31A | Ida Ertmanska Classified gene: SEC31A as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.11 | SEC31A | Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated probands reported with 3 unique homozygous variants in SEC31A and a highly syndromic presentation, resulting in early lethality. A neuron-specific sec31a knock-down in Drosophila recapitulated early lethality seen in the patients. Based on available evidence, this gene should be Green on Paediatric disorders - additional genes. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.11 | SEC31A | Ida Ertmanska Gene: sec31a has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.2 | SEC31A |
Ida Ertmanska gene: SEC31A was added gene: SEC31A was added to Fetal anomalies. Sources: Literature Q3_26_promote_green tags were added to gene: SEC31A. Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEC31A were set to 30464055; 39725565; 40508110 Phenotypes for gene: SEC31A were set to ?Halperin-Birk syndrome, OMIM:618651; neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849 Review for gene: SEC31A was set to GREEN Added comment: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. Sources: Literature |
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| Paediatric disorders - additional genes v8.10 | SEC31A |
Ida Ertmanska gene: SEC31A was added gene: SEC31A was added to Paediatric disorders - additional genes. Sources: Literature Q3_26_promote_green tags were added to gene: SEC31A. Mode of inheritance for gene: SEC31A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SEC31A were set to 30464055; 39725565; 40508110 Phenotypes for gene: SEC31A were set to ?Halperin-Birk syndrome, OMIM:618651; neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849 Review for gene: SEC31A was set to GREEN Added comment: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. Sources: Literature |
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| Intellectual disability v11.9 | SEC31A | Ida Ertmanska edited their review of gene: SEC31A: Changed publications to: 30464055, 39725565, 40508110 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.9 | SEC31A |
Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.; to: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. |
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| Early onset or syndromic epilepsy v9.68 | SEC31A |
Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.; to: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. |
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| Early onset or syndromic epilepsy v9.68 | SEC31A |
Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. Parents confirmed to be consanguineous. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.; to: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. |
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| Early onset or syndromic epilepsy v9.68 | SEC31A |
Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.; to: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. Parents confirmed to be consanguineous. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. |
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| Early onset or syndromic epilepsy v9.68 | SEC31A |
Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Focal and generalised tonic-clonic seizures were seen from birth. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage.; to: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. |
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| Early onset or syndromic epilepsy v9.68 | SEC31A | Ida Ertmanska edited their review of gene: SEC31A: Changed publications to: 30464055, 39725565, 40508110 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.68 | SEC31A |
Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.; to: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Focal and generalised tonic-clonic seizures were seen from birth. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. |
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| Early onset or syndromic epilepsy v9.68 | SEC31A | Ida Ertmanska Phenotypes for gene: SEC31A were changed from Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651 to ?Halperin-Birk syndrome, OMIM:618651; neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.67 | SEC31A | Ida Ertmanska Publications for gene: SEC31A were set to 30464055; 39725565; 40508110 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.67 | SEC31A | Ida Ertmanska Publications for gene: SEC31A were set to 30464055 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.66 | SEC31A | Ida Ertmanska Classified gene: SEC31A as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.66 | SEC31A | Ida Ertmanska Gene: sec31a has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.65 | SEC31A | Ida Ertmanska reviewed gene: SEC31A: Rating: AMBER; Mode of pathogenicity: None; Publications: 39725565, 40508110; Phenotypes: ?Halperin-Birk syndrome, OMIM:618651, neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.9 | SEC31A | Ida Ertmanska Publications for gene: SEC31A were set to 30464055 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.8 | SEC31A | Ida Ertmanska Phenotypes for gene: SEC31A were changed from Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies 618651 to ?Halperin-Birk syndrome, OMIM:618651; neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.7 | SEC31A | Ida Ertmanska edited their review of gene: SEC31A: Changed publications to: 39725565, 40508110 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.7 | SEC31A |
Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression.; to: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het. |
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| Intellectual disability v11.7 | SEC31A | Ida Ertmanska reviewed gene: SEC31A: Rating: AMBER; Mode of pathogenicity: None; Publications: 39725565; Phenotypes: ?Halperin-Birk syndrome, OMIM:618651, neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, MONDO:0032849; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.7 | PDCD6IP | Ida Ertmanska reviewed gene: PDCD6IP: Rating: AMBER; Mode of pathogenicity: None; Publications: 28322231, 32286682, 40897677; Phenotypes: ?Microcephaly 29, primary, autosomal recessive, OMIM:620047, microcephaly 29, primary, autosomal recessive, MONDO:0031060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.18 | PDCD6IP | Ida Ertmanska Publications for gene: PDCD6IP were set to 32286682; 40897677 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.17 | PDCD6IP | Ida Ertmanska edited their review of gene: PDCD6IP: Changed phenotypes to: ?Microcephaly 29, primary, autosomal recessive, OMIM:620047, microcephaly 29, primary, autosomal recessive, MONDO:0031060 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.17 | PDCD6IP | Ida Ertmanska edited their review of gene: PDCD6IP: Changed publications to: 28322231, 32286682, 40897677 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.17 | PDCD6IP | Ida Ertmanska changed review comment from: Comment on list classification: There are now 2 unrelated probands with severe microcephaly (1 progressive post-natally). A supportive animal model recaptiulating microcephaly is also available. Hence, this gene can now be promoted to Green.; to: Comment on list classification: There are now 2 unrelated probands with severe microcephaly (1 progressive post-natally). A supportive mouse model recapitulating microcephaly is also available (PMID: 28322231, old gene name Alix). Hence, this gene can now be promoted to Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.17 | PDCD6IP | Ida Ertmanska commented on gene: PDCD6IP: Comment on list classification: There are now 2 unrelated probands with severe microcephaly (1 progressive post-natally). A supportive animal model recaptiulating microcephaly is also available. Hence, this gene can now be promoted to Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.17 | PDCD6IP | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th Aug 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.17 | PDCD6IP | Ida Ertmanska Phenotypes for gene: PDCD6IP were changed from Primary microcephaly to ?Microcephaly 29, primary, autosomal recessive, OMIM:620047; microcephaly 29, primary, autosomal recessive, MONDO:0031060 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.16 | PDCD6IP | Ida Ertmanska Publications for gene: PDCD6IP were set to 32286682 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.15 | PDCD6IP |
Ida Ertmanska Tag watchlist was removed from gene: PDCD6IP. Tag Q3_26_promote_green tag was added to gene: PDCD6IP. |
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| Severe microcephaly v9.15 | PDCD6IP |
Ida Ertmanska changed review comment from: PMID: 40897677 D'Alessio et al., 2025 Report of a male individual with mild intellectual disability and microcephaly carrying a homozygous nonsense variant in PDCD6IP: NM_013374.6 c.964C>T p.(Arg322*). Heterozygous family members unaffected. Additional features of strabismus and thrombocytopenia was also noted. Proband OFC listed as 52.7cm (−2.5 SD) in table 1. At birth, his OFC was 34 cm (−0.78 SD), but at age 25 yrs, his OFC was 51.6 cm (−3.1 SD).; to: PMID: 40897677 D'Alessio et al., 2025 Report of a male individual with mild intellectual disability and acquired microcephaly carrying a homozygous nonsense variant in PDCD6IP: NM_013374.6 c.964C>T p.(Arg322*). Heterozygous family members unaffected. Additional features of strabismus and thrombocytopenia was also noted. No seizures present. Proband OFC listed as 52.7cm (−2.5 SD) in table 1. At birth, his OFC was 34 cm (−0.78 SD), but at age 25 yrs, his OFC was 51.6 cm (−3.1 SD). |
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| Severe microcephaly v9.15 | PDCD6IP | Ida Ertmanska reviewed gene: PDCD6IP: Rating: GREEN; Mode of pathogenicity: None; Publications: 40897677; Phenotypes: ?Microcephaly 29, primary, autosomal recessive, OMIM:620047; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.26 | PCLO |
Ida Ertmanska changed review comment from: PMID: 42038819 Baneshi et al., 2025 Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES. CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed. PMID: 40661989 Lertsakulbunlue et al., 2025 Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis. PMID: 30287594 Chitre et al., 2018 Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19). Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter). Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs. PMID: 25832664 Ahmed et al., 2015 Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant. FUNCTIONAL EVIDENCE: PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).; to: PMID: 42038819 Baneshi et al., 2025 Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia (usure on age of onset), behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES. CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed. PMID: 40661989 Lertsakulbunlue et al., 2025 Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis. PMID: 30287594 Chitre et al., 2018 Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19). Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter). Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs. PMID: 25832664 Ahmed et al., 2015 Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant. FUNCTIONAL EVIDENCE: PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026). |
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| Early onset or syndromic epilepsy v9.65 | PCLO | Ida Ertmanska changed review comment from: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. There is a supportive rat model showing that pclo knock-out results in reduced brain size, impaired motor coordination, and seizures. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.26 | PCLO | Ida Ertmanska changed review comment from: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and cerebellar atrophy / hypoplasia, plus 1 additional case with mild ataxia. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and cerebellar atrophy / hypoplasia, plus 1 additional case with mild ataxia. There is a supportive rat model showing that pclo knock-out results in reduced brain size and impaired motor coordination. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.26 | PCLO | Ida Ertmanska Phenotypes for gene: PCLO were changed from Pontocerebellar Hypoplasia type 3; Pontocerebellar hypoplasia 3 homozygous non-sense variant identified in the affected individuals of a single pedigree. to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.25 | PCLO | Ida Ertmanska Publications for gene: PCLO were set to PMID: 25832664 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.24 | PCLO | Ida Ertmanska Classified gene: PCLO as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.24 | PCLO | Ida Ertmanska Gene: pclo has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.23 | PCLO | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: PCLO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.23 | PCLO | Ida Ertmanska commented on gene: PCLO: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and cerebellar atrophy / hypoplasia, plus 1 additional case with mild ataxia. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.23 | PCLO | Ida Ertmanska reviewed gene: PCLO: Rating: GREEN; Mode of pathogenicity: None; Publications: 25832664, 30287594, 32122952, 40661989, 42038819; Phenotypes: Pontocerebellar hypoplasia, type 3, OMIM:608027, PEHO syndrome, MONDO:0009841, progressive encephalopathy with edema, hypsarrhythmia and optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.7 | PCLO | Ida Ertmanska commented on gene: PCLO: Comment on list classification: Though there are now at least 3 unrelated families reported in literature with biallelic PCLO variants and severe psychomotor developmental delay, this is likely secondary to pontocerebellar hypoplasia and early-onset epilepsy. Hence, this gene should remain Red on the Intellectual disability panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.7 | PCLO | Ida Ertmanska reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: None; Publications: 25832664, 30287594, 32122952, 40661989, 42038819; Phenotypes: Pontocerebellar hypoplasia, type 3, OMIM:608027, PEHO syndrome, MONDO:0009841, progressive encephalopathy with edema, hypsarrhythmia and optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.65 | PCLO |
Ida Ertmanska changed review comment from: PMID: 42038819 Baneshi et al., 2025 Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES. CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed. PMID: 40661989 Lertsakulbunlue et al., 2025 Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis. PMID: 30287594 Chitre et al., 2018 Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19). Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter). Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs. PMID: 25832664 Ahmed et al., 2015 Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant. FUNCTIONAL EVIDENCE: PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).; to: PMID: 42038819 Baneshi et al., 2025 Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES. CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed. PMID: 40661989 Lertsakulbunlue et al., 2025 Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis. PMID: 30287594 Chitre et al., 2018 Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19). Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter). Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs. PMID: 25832664 Ahmed et al., 2015 Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant. FUNCTIONAL EVIDENCE: PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026). |
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| Early onset or syndromic epilepsy v9.65 | PCLO | Ida Ertmanska edited their review of gene: PCLO: Changed publications to: 25832664, 30287594, 32122952, 40661989, 42038819 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.65 | PCLO |
Ida Ertmanska changed review comment from: PMID: 42038819 Baneshi et al., 2025 Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES. CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed. PMID: 40661989 Lertsakulbunlue et al., 2025 Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis. PMID: 30287594 Chitre et al., 2018 Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19). Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter). Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs. PMID: 25832664 Ahmed et al., 2015 Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).; to: PMID: 42038819 Baneshi et al., 2025 Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia, behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES. CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed. PMID: 40661989 Lertsakulbunlue et al., 2025 Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis. PMID: 30287594 Chitre et al., 2018 Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19). Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter). Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs. PMID: 25832664 Ahmed et al., 2015 Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant. FUNCTIONAL EVIDENCE: PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026). |
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| Early onset or syndromic epilepsy v9.65 | PCLO | Ida Ertmanska Phenotypes for gene: PCLO were changed from to Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.64 | PCLO | Ida Ertmanska Publications for gene: PCLO were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.63 | PCLO | Ida Ertmanska Mode of inheritance for gene: PCLO was changed from to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.62 | PCLO | Ida Ertmanska Classified gene: PCLO as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.62 | PCLO | Ida Ertmanska Added comment: Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.62 | PCLO | Ida Ertmanska Gene: pclo has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.61 | PCLO | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: PCLO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.61 | PCLO | Ida Ertmanska reviewed gene: PCLO: Rating: GREEN; Mode of pathogenicity: None; Publications: 25832664, 30287594, 40661989, 42038819; Phenotypes: Pontocerebellar hypoplasia, type 3, OMIM:608027, PEHO syndrome, MONDO:0009841, progressive encephalopathy with edema, hypsarrhythmia and optic atrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arrhythmogenic right ventricular cardiomyopathy v3.18 | JUP | Matthew Edwards changed review comment from: On CGGL Royal Brompton ACM panel (although only VUS reported so far). Definitive ARVC gene; to: On CGGL Royal Brompton ACM panel (although only VUS reported so far). Definitive ARVC/NAXOS disease gene, although unclear if definitively causes dominant disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe insulin resistance and lipodystrophy syndromes v5.4 | PSMB8 | Achchuthan Shanmugasundram Phenotypes for gene: PSMB8 were changed from Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040 to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; proteasome-associated autoinflammatory syndrome 1, MONDO:0054698 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe insulin resistance and lipodystrophy syndromes v5.3 | PSMB8 | Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed phenotypes to: Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040, proteasome-associated autoinflammatory syndrome 1, MONDO:0054698 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.20 | PSMB8 |
Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with proteasome-associated autoinflammatory syndrome and immunodeficiency. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. |
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| Autoinflammatory disorders v3.20 | PSMB8 | Achchuthan Shanmugasundram Mode of inheritance for gene: PSMB8 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.19 | PSMB8 | Achchuthan Shanmugasundram Phenotypes for gene: PSMB8 were changed from Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040 to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; proteasome-associated autoinflammatory syndrome 1, MONDO:0054698; Immunodeficiency, HP:0002721 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.18 | PSMB8 | Achchuthan Shanmugasundram Publications for gene: PSMB8 were set to 21852578; 21953331; 20534754; 20159315; 21881205; 21129723 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.17 | PSMB8 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: PSMB8. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.17 | PSMB8 | Achchuthan Shanmugasundram reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: 41253591, 42167218; Phenotypes: Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040, proteasome-associated autoinflammatory syndrome 1, MONDO:0054698, Immunodeficiency, HP:0002721; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes, directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 | PSMB8 | Achchuthan Shanmugasundram Publications for gene: PSMB8 were set to 21881205; 20159315; 21953331; 21129723; 20534754; 21852578; 42167218 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with immunodeficiency and inflammation. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.; to: Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with proteasome-associated autoinflammatory syndrome and immunodeficiency. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence available (>3 unrelated families and functional work) for the association of monoallelic PSMB8 variants with immunodeficiency and inflammation. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.; to: Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with immunodeficiency and inflammation. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 | Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed publications to: 41253591, 42167218 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 |
Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available (>3 unrelated families and functional work) for the association of monoallelic PSMB8 variants with immunodeficiency and inflammation. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 | Achchuthan Shanmugasundram Mode of inheritance for gene: PSMB8 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.100 | PSMB8 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: PSMB8 was changed from None to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.99 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).; to: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.99 | PSMB8 | Achchuthan Shanmugasundram edited their review of gene: PSMB8: Changed mode of pathogenicity: Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.99 | PSMB8 | Achchuthan Shanmugasundram Publications for gene: PSMB8 were set to 21881205; 20159315; 21953331; 21129723; 20534754; 21852578 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.98 | PSMB8 | Achchuthan Shanmugasundram Phenotypes for gene: PSMB8 were changed from Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; Autoinflammation, lipodystrophy, and dermatosis syndrome; Contractures, panniculitis, ICC, fevers; Autoinflammatory Disorders; CANDLE syndrome to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; proteasome-associated autoinflammatory syndrome 1, MONDO:0054698; Immunodeficiency, HP:0002721 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 | PSMB8 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: PSMB8. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 | PSMB8 | Achchuthan Shanmugasundram reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: None; Publications: 42167218; Phenotypes: Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040, proteasome-associated autoinflammatory syndrome 1, MONDO:0054698, Immunodeficiency, HP:0002721; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiac arrhythmias - additional genes v3.13 | STS |
William Davies gene: STS was added gene: STS was added to Cardiac arrhythmias - additional genes. Sources: Research,Literature Mode of inheritance for gene: STS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: STS were set to PMIDs: 32139392; 36379544; 39158681; 39150468; 40688208; 40062371; 39912958; 28795252 and doi: 10.64898/2026.07.22.739997v1 Phenotypes for gene: STS were set to Atrial fibrillation/flutter; supraventricular tachycardia; bradycardia; ventricular ectopic beats; QT interval alteration Penetrance for gene: STS were set to Incomplete Mode of pathogenicity for gene: STS was set to Other Review for gene: STS was set to RED Added comment: Four independent and converging lines of evidence currently support inclusion of STS (Xp22.31) as a novel candidate gene for arrhythmias (particularly in males): 1. Deletion Copy Number Variants encompassing STS are associated with increased risk of a variety of heart rhythm abnormalities: • Middle-aged male deletion carriers are at ~4x risk of being diagnosed with atrial fibrillation compared to age/sex-matched non-carriers, and self-report higher levels of arrhythmia/atrial flutter (PMID: 32139392) • Paroxysmal supraventricular tachycardia in 2 year old male deletion carrier (PMID: 29569268) • Diagnoses of brady- and tachycardia and atrial fibrillation self-reported by male and female deletion carriers (PMID: 36379544) • Exercise-induced atrial fibrillation presenting at 16 and 23 years in 25 year old male deletion carrier with ongoing sinus bradycardia (PMIDs: 39158681 and 39150468) • 16 year old male deletion carrier presenting with history of sinus bradycardia from 5 years, shortened QT interval and polymorphic ventricular extrasystole (up to 9% of heartbeats); 2.5 year old male deletion carrier with supraventricular pacemaker migration, mild bradycardia with shortened QT interval, and significant arrhythmia with a heart rate ranging from 76–118 bpm (PMID: 40688208) • Sudden cardiac arrest with ventricular fibrillation in 17 year old male deletion carrier. ECG showed a wandering atrial pacemaker, ST-segment elevation, and T-wave inversion, frequent polymorphic ventricular extrasystoles (VES), ventricular couplet, 1 3-beat 160/min ventricular tachycardia, and 131 ventricular bigeminies (PMID: 40062371) • Three adult male deletion carriers with a history of (paroxysmal) atrial fibrillation and supraventricular ectopic beats; two presented with ongoing frequent ventricular ectopic beats (PMID: 39912958) 2. Genetic association analysis across Xp22.31 highlights an excess of common risk variants for idiopathic atrial fibrillation within STS in a large middle-aged male sample of 4556 cases and 163,499 controls (PMID: 36379544) 3. Systemic inhibition of the STS enzyme in a cohort of 10 patients with early breast cancer pre-screened to exclude a history of cardiac arrhythmia resulted in three Grade 2 adverse events (two related to abnormal ECG and one to tachycardia) and one Grade 1 adverse event (prolonged QT)(PMID: 28795252). 4. In ex vivo ECG, the hearts of mice with a small Sts-specific genetic deletion and >95% loss of enzyme activity show evidence for an increased frequency of abnormal rhythms (notably ventricular ectopics) and for longer runs of abnormal beats (doi:10.64898/2026.07.22.739997v1) Sources: Research, Literature |
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| Early onset or syndromic epilepsy v9.61 | ELAVL2 | Achchuthan Shanmugasundram Classified gene: ELAVL2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.61 | ELAVL2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (at least four unrelated cases and functional studies) available for the association of monoallelic ELAVL2 variants with epilepsy. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.61 | ELAVL2 | Achchuthan Shanmugasundram Gene: elavl2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.60 | ELAVL2 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: ELAVL2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.1 | MMP9 | Ida Ertmanska reviewed gene: MMP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 19615667, 28342220, 34407464, 36035187; Phenotypes: Metaphyseal anadysplasia 2, OMIM:613073, metaphyseal anadysplasia 2, MONDO:0013113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.3 | MMP9 | Ida Ertmanska commented on gene: MMP9: Comment on list classification: There are now 4 unrelated individuals reported with biallelic MMP9 variants and Metaphyseal anadysplasia. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.1 | MMP9 | Ida Ertmanska Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.1 | MMP9 | Ida Ertmanska Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.1 | MMP9 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: MMP9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.1 | MMP9 | Ida Ertmanska reviewed gene: MMP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 34407464, 36035187; Phenotypes: Metaphyseal anadysplasia 2, OMIM:613073, metaphyseal anadysplasia 2, MONDO:0013113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.3 | MMP9 | Ida Ertmanska Phenotypes for gene: MMP9 were changed from Metaphyseal anadysplasia 2 613073 to Metaphyseal anadysplasia 2, OMIM:613073; metaphyseal anadysplasia 2, MONDO:0013113 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.2 | MMP9 | Ida Ertmanska Publications for gene: MMP9 were set to 28342220; 19615667 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.1 | MMP9 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: MMP9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.1 | MMP9 | Ida Ertmanska reviewed gene: MMP9: Rating: GREEN; Mode of pathogenicity: None; Publications: 34407464, 36035187; Phenotypes: Metaphyseal anadysplasia 2, OMIM:613073, metaphyseal anadysplasia 2, MONDO:0013113; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.7 | LMAN2L |
Ida Ertmanska Tag watchlist was removed from gene: LMAN2L. Tag Q3_26_promote_green tag was added to gene: LMAN2L. |
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| Intellectual disability v11.7 | LMAN2L | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th Aug 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.7 | LMAN2L | Ida Ertmanska Phenotypes for gene: LMAN2L were changed from Intellectual disability; epilepsy to ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863; ?Intellectual developmental disorder, autosomal recessive 52, OMIM:61688; intellectual disability, autosomal recessive 52, MONDO:0014815; intellectual developmental disorder, autosomal dominant 69, MONDO:0029465 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.60 | LMAN2L | Ida Ertmanska edited their review of gene: LMAN2L: Changed phenotypes to: ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863, ?Intellectual developmental disorder, autosomal recessive 52, OMIM:61688, intellectual disability, autosomal recessive 52, MONDO:0014815, intellectual developmental disorder, autosomal dominant 69, MONDO:0029465 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.60 | LMAN2L | Ida Ertmanska edited their review of gene: LMAN2L: Changed phenotypes to: ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863, ?Intellectual developmental disorder, autosomal recessive 52, OMIM:61688, intellectual disability, autosomal recessive 52, MONDO:0014815 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.6 | LMAN2L | Ida Ertmanska Publications for gene: LMAN2L were set to 31020005; 26566883 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.5 | LMAN2L | Ida Ertmanska Mode of inheritance for gene: LMAN2L was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.4 | LMAN2L | Ida Ertmanska commented on gene: LMAN2L: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and severe GDD/ID. There is also one pedigree reported with a heterozygous LMAN2L variant segregating with ID. Hence, this gene can be promoted to Green at the next update, with MOI set to 'BIALLELIC, autosomal or pseudoautosomal', until more evidence emerges for the dominant association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.60 | LMAN2L | Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and early-onset epilepsy. There is also one pedigree reported with a heterozygous LMAN2L variant segregating with tonic clonic seizures. Hence, this gene can be promoted to Green at the next update, with MOI set to 'BIALLELIC, autosomal or pseudoautosomal', until more evidence emerges for the dominant association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.60 | ELAVL2 |
Achchuthan Shanmugasundram gene: ELAVL2 was added gene: ELAVL2 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: ELAVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ELAVL2 were set to 42556336 Phenotypes for gene: ELAVL2 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: ELAVL2 was set to GREEN Added comment: PMID:42556336 (2026) reported 13 previously unpublished individuals, plus three previously reported cases, with de novo heterozygous ELAVL2 variants presenting with a neurodevelopmental disorder in which epilepsy was a recurrent, though not universal, feature—seizures were reported in 4 of 13 newly described individuals (1/7 with truncating/structural variants and 3/6 with missense variants), comprising absence, febrile, tonic-clonic, and spasms (West syndrome in one individual with a missense variant). All affected individuals additionally presented with developmental delay, intellectual disability of varying severity, motor and speech delay, autism spectrum diagnoses, sleep disturbance, sensory processing abnormalities (hyper- or hyposensitivity to sound, texture, and light), and behavioural/emotional dysregulation. Drosophila loss-of-function models of the ELAVL2 ortholog fne (null mutant and pan-neuronal RNAi knockdown) showed significantly increased seizure-like behaviour (both duration and frequency) following mechanical induction, establishing a causal functional link between ELAVL2 loss-of-function and seizure susceptibility. This gene has not yet been associated with relevant phenotypes either in OMIM, ClinGen or Gene2Phenotype (last accessed 13 August 2026). Sources: Literature |
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| Intellectual disability v11.4 | LMAN2L | Ida Ertmanska reviewed gene: LMAN2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 37667433, 40221759; Phenotypes: ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863, ?Intellectual developmental disorder, autosomal recessive 52, OMIM:616887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.59 | LMAN2L | Ida Ertmanska commented on gene: LMAN2L: Comment on list classification: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and early-onset epilepsy. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.59 | LMAN2L | Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th Aug 2026. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.59 | LMAN2L | Ida Ertmanska Phenotypes for gene: LMAN2L were changed from Intellectual disability; Epilepsy to ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863; ?Intellectual developmental disorder, autosomal recessive 52, OMIM:616887; intellectual developmental disorder, autosomal dominant 69, MONDO:0029465; intellectual disability, autosomal recessive 52, MONDO:0014815 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.58 | LMAN2L | Ida Ertmanska Publications for gene: LMAN2L were set to 31020005; 26566883 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.57 | LMAN2L | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: LMAN2L. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.57 | LMAN2L | Ida Ertmanska reviewed gene: LMAN2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 37667433, 40221759; Phenotypes: ?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863, ?Intellectual developmental disorder, autosomal recessive 52, OMIM:616887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.4 | ELAVL2 | Achchuthan Shanmugasundram Classified gene: ELAVL2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.4 | ELAVL2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic variants in this gene with a neurodevelopmental disorder with intellectual disability as the primary feature of the disorder. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.4 | ELAVL2 | Achchuthan Shanmugasundram Gene: elavl2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.3 | ELAVL2 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: ELAVL2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.41 | DIAPH3 | Ida Ertmanska Mode of pathogenicity for gene: DIAPH3 was changed from Other - please provide details in the comments to None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.40 | DIAPH3 | Ida Ertmanska changed review comment from: Comment on list classification: There are now more than 3 unrelated families reported where monoallelic DIAPH3 variants have been reported to co-segregate with dominant hearing loss. There is only one pedigree reported where some affected individuals were homozygous. Hence, this gene can be promoted to Green on Monogenic hearing loss, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; to: Comment on list classification: There are now more than 3 unrelated families reported where monoallelic DIAPH3 variants have been reported to co-segregate with dominant hearing loss. There is only one pedigree reported where some affected individuals were heterozygous and some homozygous (no difference in phenotype). Hence, this gene can be promoted to Green on Monogenic hearing loss, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, until more evidence emerges for biallelic cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.40 | DIAPH3 | Ida Ertmanska commented on gene: DIAPH3: Comment on list classification: There are now more than 3 unrelated families reported where monoallelic DIAPH3 variants have been reported to co-segregate with dominant hearing loss. There is only one pedigree reported where some affected individuals were homozygous. Hence, this gene can be promoted to Green on Monogenic hearing loss, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.40 | DIAPH3 | Ida Ertmanska Phenotypes for gene: DIAPH3 were changed from Auditory neuropathy, autosomal dominant, 1, 609129 to Auditory neuropathy, autosomal dominant 1, OMIM:609129; autosomal dominant auditory neuropathy 1, MONDO:0012196 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.39 | DIAPH3 | Ida Ertmanska Publications for gene: DIAPH3 were set to 14767582; 15520414; 18755006; 19457867; 20624953; 20624953; 27658576 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.38 | DIAPH3 | Ida Ertmanska Mode of inheritance for gene: DIAPH3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.37 | DIAPH3 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DIAPH3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.37 | DIAPH3 | Ida Ertmanska reviewed gene: DIAPH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38860500, 39767564, 40040362, 41511813; Phenotypes: Auditory neuropathy, autosomal dominant 1, OMIM:609129, autosomal dominant auditory neuropathy 1, MONDO:0012196; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.57 | DHX16 | Ida Ertmanska commented on gene: DHX16: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). 3 unrelated individuals presented with infantile spasms / epilepsy. Hence, this gene should be promoted to Green on Early onset or syndromic epilepsy at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.57 | DHX16 |
Ida Ertmanska Tag watchlist was removed from gene: DHX16. Tag Q3_26_promote_green tag was added to gene: DHX16. |
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| Early onset or syndromic epilepsy v9.57 | DHX16 | Ida Ertmanska edited their review of gene: DHX16: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.57 | DHX16 | Ida Ertmanska reviewed gene: DHX16: Rating: RED; Mode of pathogenicity: None; Publications: 31256877, 36212160, 36211162, 37574199, 37664979, 40141454, 41555919; Phenotypes: 31256877, 36212160, 36211162, 37574199, 37664979, 40141454, 41555919; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.37 | DHX16 | Ida Ertmanska Classified gene: DHX16 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.37 | DHX16 | Ida Ertmanska Added comment: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). Moreover, severe hearing loss was the main / presenting finding in some patients. Hence, this gene should be promoted to Green for Monogenic hearing loss at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.37 | DHX16 | Ida Ertmanska Gene: dhx16 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.17 | DHX16 | Ida Ertmanska Classified gene: DHX16 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.17 | DHX16 | Ida Ertmanska Added comment: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). Moreover, retinitis pigmentosa was the main / presenting finding in some patients. Hence, this gene should be promoted to Green for Retinal disorders at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.17 | DHX16 | Ida Ertmanska Gene: dhx16 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.36 | DHX16 |
Ida Ertmanska gene: DHX16 was added gene: DHX16 was added to Monogenic hearing loss. Sources: Literature Q3_26_promote_green tags were added to gene: DHX16. Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DHX16 were set to 31256877; 36212160; 36211162; 37574199; 37664979; 40141454; 41555919 Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 Review for gene: DHX16 was set to GREEN Added comment: PMID: 41555919 Wang et al., 2026 2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases. PMID: 40326698 Clay et al., 2025 3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported. PMID: 40141454 Kalampokini et al., 2025 Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy. PMID: 37664979 Drackley et al., 2023 Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative. Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant. PMID: 37574199 Hautakangas et al., 2023 Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3 years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents. PMID: 36211162 Archana et al., 2022 Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown). PMID: 36212160 Park et al., 2022 Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported. PMID: 31256877 Paine et al., 2019 Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome. P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC. P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His. P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL. P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; Tapetoretinal degeneration and total vision loss; SNHL; contractures. Sources: Literature |
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| Retinal disorders v9.16 | DHX16 |
Ida Ertmanska gene: DHX16 was added gene: DHX16 was added to Retinal disorders. Sources: Literature Q3_26_promote_green tags were added to gene: DHX16. Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DHX16 were set to 31256877; 36212160; 36211162; 37574199; 37664979; 40141454; 41555919 Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 Review for gene: DHX16 was set to GREEN Added comment: PMID: 41555919 Wang et al., 2026 2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases. PMID: 40326698 Clay et al., 2025 3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported. PMID: 40141454 Kalampokini et al., 2025 Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy. PMID: 37664979 Drackley et al., 2023 Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative. Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant. PMID: 37574199 Hautakangas et al., 2023 Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3 years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents. PMID: 36211162 Archana et al., 2022 Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown). PMID: 36212160 Park et al., 2022 Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported. PMID: 31256877 Paine et al., 2019 Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome. P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC. P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His. P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL. P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; Tapetoretinal degeneration and total vision loss; SNHL; contractures. Sources: Literature |
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| Congenital myopathy v7.80 | DHX16 | Ida Ertmanska Phenotypes for gene: DHX16 were changed from Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 to Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.79 | DHX16 | Ida Ertmanska Publications for gene: DHX16 were set to 31256877 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.78 | DHX16 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DHX16. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.78 | DHX16 | Ida Ertmanska changed review comment from: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinal disease (9/12). Hence, this gene should be promoted to Green for Congenital myopathy at the next update.; to: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). 5 probands presented with congenital myopathy / severe congenital hypotonia. Hence, this gene should be promoted to Green for Congenital myopathy at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.78 | DHX16 |
Ida Ertmanska changed review comment from: PMID: 41555919 Wang et al., 2026 2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases. PMID: 40326698 Clay et al., 2025 3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported. PMID: 40141454 Kalampokini et al., 2025 Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy. PMID: 37664979 Drackley et al., 2023 Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative. Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant. PMID: 37574199 Hautakangas et al., 2023 Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3 years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents. PMID: 36211162 Archana et al., 2022 Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown). PMID: 36212160 Park et al., 2022 Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported. PMID: 31256877 Paine et al., 2019 Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome. P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC. P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His. P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL. P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; total vision loss; SNHL; contractures.; to: PMID: 41555919 Wang et al., 2026 2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases. PMID: 40326698 Clay et al., 2025 3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported. PMID: 40141454 Kalampokini et al., 2025 Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy. PMID: 37664979 Drackley et al., 2023 Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative. Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant. PMID: 37574199 Hautakangas et al., 2023 Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3 years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents. PMID: 36211162 Archana et al., 2022 Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown). PMID: 36212160 Park et al., 2022 Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported. PMID: 31256877 Paine et al., 2019 Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome. P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC. P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His. P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL. P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; Tapetoretinal degeneration and total vision loss; SNHL; contractures. |
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| Congenital myopathy v7.78 | DHX16 | Ida Ertmanska commented on gene: DHX16: Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinal disease (9/12). Hence, this gene should be promoted to Green for Congenital myopathy at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.78 | DHX16 | Ida Ertmanska edited their review of gene: DHX16: Changed phenotypes to: Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733, neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.78 | DHX16 | Ida Ertmanska edited their review of gene: DHX16: Changed publications to: 31256877, 36212160, 36211162, 37574199, 37664979, 40141454, 41555919 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.78 | DHX16 |
Ida Ertmanska changed review comment from: PMID: 41555919 Wang et al., 2026 2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases. PMID: 40141454 Kalampokini et al., 2025 Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy. PMID: 37664979 Drackley et al., 2023 Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative. Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant. PMID: 37574199 Hautakangas et al., 2023 Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3 years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents. PMID: 36211162 Archana et al., 2022 Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).; to: PMID: 41555919 Wang et al., 2026 2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases. PMID: 40326698 Clay et al., 2025 3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported. PMID: 40141454 Kalampokini et al., 2025 Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy. PMID: 37664979 Drackley et al., 2023 Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative. Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant. PMID: 37574199 Hautakangas et al., 2023 Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3 years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents. PMID: 36211162 Archana et al., 2022 Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown). PMID: 36212160 Park et al., 2022 Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported. PMID: 31256877 Paine et al., 2019 Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome. P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC. P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His. P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL. P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; total vision loss; SNHL; contractures. |
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| Intellectual disability v11.3 | ELAVL2 |
Achchuthan Shanmugasundram gene: ELAVL2 was added gene: ELAVL2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ELAVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ELAVL2 were set to 42556336 Phenotypes for gene: ELAVL2 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: ELAVL2 was set to GREEN Added comment: PMID:42556336 (2026) reported 13 previously unpublished individuals, plus three previously reported cases, presenting with developmental delay, intellectual disability of varying severity, autism spectrum disorder, seizures (absence, febrile, tonic-clonic), sleep disturbances (insomnia, sleep apnea), sensory processing abnormalities (hyper- and hyposensitivity to sound, texture, light), and behavioral/emotional dysregulation with attention deficits. Among the 13 newly described individuals, ID severity was mild in 4, moderate in 1, severe in 2, borderline in 2, and unspecified learning difficulties in 2; one individual had no ID, and one was not formally assessed. These individuals were identified with de novo heterozygous variants in ELAVL2, including two structural variants (a pericentric inversion and a reciprocal translocation disrupting the gene), five truncating variants (c.142C>T/p.Gln48*, c.166_167del/p.Lys56Glufs8, c.189dup/p.Glu64, c.380dupT/p.Leu127Phefs48, c.657C>G/p.Tyr219), and six missense variants (c.154C>A/p.Gln52Lys, c.159G>C/p.Glu53Asp, c.475G>A/p.Asp159Asn, c.527G>A/p.Arg176Gln, c.695A>C/p.Gln232Pro, c.913G>A/p.Val305Met). ID was present in 3/7 individuals with truncating/structural variants versus 6/6 individuals with missense variants, with the most severely affected individual (severe ID, walking at 6 years, first words at 6 years) also carrying a pathogenic NF1 variant that may have contributed to disease severity. Motor delay was seen in 6/7 individuals with truncating/structural variants and 5/6 with missense variants, while speech delay occurred in 5/7 and 6/6, respectively; one adult female with a structural variant additionally presented with premature ovarian insufficiency. This gene has not yet been associated with relevant phenotypes either in OMIM, ClinGen or Gene2Phenotype (last accessed 13 August 2026). Sources: Literature |
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| Congenital myopathy v7.78 | DHX16 | Ida Ertmanska edited their review of gene: DHX16: Changed publications to: 36211162, 37574199, 37664979, 40141454, 41555919 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.78 | DHX16 |
Ida Ertmanska changed review comment from: PMID: 41555919 Wang et al., 2026 2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases. PMID: 40141454 Kalampokini et al., 2025 Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss, retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant PMID: 37664979 Drackley et al., 2023 Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative. Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant. PMID: 37574199 Hautakangas et al., 2023 Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3 years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents. PMID: 36211162 Archana et al., 2022 Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).; to: PMID: 41555919 Wang et al., 2026 2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases. PMID: 40141454 Kalampokini et al., 2025 Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy. PMID: 37664979 Drackley et al., 2023 Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative. Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant. PMID: 37574199 Hautakangas et al., 2023 Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3 years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents. PMID: 36211162 Archana et al., 2022 Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown). |
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| Congenital myopathy v7.78 | DHX16 | Ida Ertmanska reviewed gene: DHX16: Rating: GREEN; Mode of pathogenicity: None; Publications: 36211162, 37574199, 37664979, 41555919; Phenotypes: Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.2 | COPB1 | Ida Ertmanska Publications for gene: COPB1 were set to 33632302 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.1 | COPB1 |
Ida Ertmanska Tag watchlist was removed from gene: COPB1. Tag Q3_26_promote_green tag was added to gene: COPB1. |
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| Severe microcephaly v9.15 | COPB1 | Ida Ertmanska Publications for gene: COPB1 were set to 33632302 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.1 | COPB1 | Ida Ertmanska reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.14 | COPB1 | Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Luke Stuart, there are now 8 individuals from 3 unrelated families reported in literature with biallelic COPB1 variants and Baralle-Macken syndrome. 3 unrelated probands reported had severe microcephaly (over 3SD below average, or below the 1st percentile). There is also a Xenopus model, supportive of the gene-disease association. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: As reviewed by Luke Stuart, there are now 8 individuals from 3 unrelated families reported in literature with biallelic COPB1 variants and Baralle-Macken syndrome. 3 unrelated probands reported had severe microcephaly (over 3SD below average, or OFC below the 1st percentile). There is also a Xenopus model, supportive of the gene-disease association. Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.14 | COPB1 | Ida Ertmanska reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.14 | COPB1 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: COPB1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.7 | COPB1 | Ida Ertmanska edited their review of gene: COPB1: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.7 | COPB1 | Ida Ertmanska commented on gene: COPB1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.7 | COPB1 | Ida Ertmanska Publications for gene: COPB1 were set to 33632302 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.6 | COPB1 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: COPB1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 | NFATC1 | Achchuthan Shanmugasundram Classified gene: NFATC1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 | NFATC1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case and functional evidence available in support of the association of NFATC1 with immunodeficiency. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.97 | NFATC1 | Achchuthan Shanmugasundram Gene: nfatc1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.96 | NFATC1 | Achchuthan Shanmugasundram Phenotypes for gene: NFATC1 were changed from recurrent infections; hypogammaglobulinemia; decreased antibody responses to inborn error of immunity, MONDO:0003778 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.95 | NFATC1 | Achchuthan Shanmugasundram reviewed gene: NFATC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37249233; Phenotypes: inborn error of immunity, MONDO:0003778; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.95 | NFATC2 | Achchuthan Shanmugasundram Classified gene: NFATC2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.95 | NFATC2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated cases published with biallelic NFATC2 variants and with a relevant phenotype. They displayed phenotypic variability with both displaying lymphoproliferative disorder, but only one with skeletal phenotype. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.95 | NFATC2 | Achchuthan Shanmugasundram Gene: nfatc2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.94 | NFATC2 | Achchuthan Shanmugasundram Publications for gene: NFATC2 were set to 35789258 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.93 | NFATC2 | Achchuthan Shanmugasundram Phenotypes for gene: NFATC2 were changed from progressive joint contractures; osteochondromas; B cell malignancy; diarrhea; chronic lung disease; hypogammaglobulinemia to ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369; lymphoproliferative syndrome, MONDO:0016537 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.92 | NFATC2 | Achchuthan Shanmugasundram reviewed gene: NFATC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35789258, 38427060; Phenotypes: ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232, joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369, lymphoproliferative syndrome, MONDO:0016537; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.11 | ATP1A3 | Achchuthan Shanmugasundram Classified gene: ATP1A3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.11 | ATP1A3 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are nine unrelated cases reported with the same recurrent heterozygous variant and functional evidence available in support of the association of this gene with a novel disorder with spasticity and ID/ DD. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.11 | ATP1A3 | Achchuthan Shanmugasundram Gene: atp1a3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.10 | ATP1A3 |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: ATP1A3. Tag Q3_26_promote_green tag was added to gene: ATP1A3. |
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| Hereditary spastic paraplegia, childhood onset v9.10 | ATP1A3 | Achchuthan Shanmugasundram Phenotypes for gene: ATP1A3 were changed from spasticity; developmental delay; intellectual disability to Alternating hemiplegia of childhood 2, OMIM:614820; alternating hemiplegia of childhood 2, MONDO:0013900; Developmental and epileptic encephalopathy 99, OMIM:619606; developmental and epileptic encephalopathy 99, MONDO:0030473; Spasticity, HP:0001257; intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.9 | ATP1A3 | Achchuthan Shanmugasundram Publications for gene: ATP1A3 were set to PMID: 37043503 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.8 | ATP1A3 | Achchuthan Shanmugasundram reviewed gene: ATP1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37043503; Phenotypes: Alternating hemiplegia of childhood 2, OMIM:614820, alternating hemiplegia of childhood 2, MONDO:0013900, Developmental and epileptic encephalopathy 99, OMIM:619606, developmental and epileptic encephalopathy 99, MONDO:0030473, Spasticity, HP:0001257, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease v13.35 | Achchuthan Shanmugasundram Panel version 13.34 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic renal disease v13.6 | Achchuthan Shanmugasundram Panel version 13.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cerebral malformation v16.12 | Ida Ertmanska Panel version 16.11 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult-onset neurological disorders v9.20 | Ida Ertmanska Panel version 9.19 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other rare neuromuscular disorders v31.136 | Achchuthan Shanmugasundram Panel version 31.135 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare multisystem ciliopathy Super panel v22.3 | Ida Ertmanska Panel version 22.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypotonic infant v47.2 | Arina Puzriakova Panel version 47.1 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders v76.2 | Ida Ertmanska Panel version 76.1 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained death in infancy and sudden unexplained death in childhood v23.106 | Arina Puzriakova Panel version 23.105 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia and cerebellar anomalies, childhood onset v23.33 | Achchuthan Shanmugasundram Panel version 23.32 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sudden unexplained death or survivors of a cardiac event v23.19 | Arina Puzriakova Panel version 23.18 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, childhood onset v32.3 | Achchuthan Shanmugasundram Panel version 32.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiac arrhythmias v14.32 | Arina Puzriakova Panel version 14.31 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.1 | Arina Puzriakova Panel version 11.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v11.0 | Arina Puzriakova promoted panel to version 11.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.10 | Arina Puzriakova Panel version 1.9 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sarcoma of possible germline origin v1.3 | Arina Puzriakova Panel version 1.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Embryonal tumour of possible germline origin v1.3 | Arina Puzriakova Panel version 1.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| NICE approved PARP inhibitor treatment v1.4 | Arina Puzriakova Panel version 1.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Unexplained young onset end-stage renal disease - additional genes v2.2 | Arina Puzriakova Panel version 2.1 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Diagnostic v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Glutaric acidaemia type 1 - Diagnostic v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Isovaleric acidaemia - Diagnostic v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic short stature v2.9 | Arina Puzriakova Panel version 2.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Wiskott-Aldrich syndrome v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Wilson disease v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| von Willebrand disease v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Von Hippel Lindau syndrome v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Variegate porphyria v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tuberous sclerosis v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thiamine metabolism dysfunction syndrome 2 v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thanatophoric dysplasia v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sickle cell, thalassaemia and other haemoglobinopathies v2.12 | Arina Puzriakova Panel version 2.11 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tay-Sachs disease v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Syndromic and non syndromic craniosynostosis involving midline sutures v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subcutaneous panniculitis T-cell lymphoma (SPTCL) v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Spinal muscular atrophy - Diagnostic v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Smith-Lemli-Opitz syndrome v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sitosterolaemia v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short stature - SHOX deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe combined immunodeficiency with PNP deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe combined immunodeficiency with adenosine deaminase deficiency v1.7 | Arina Puzriakova Panel version 1.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Segmental or atypical neurofibromatosis type 1 testing v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SCID with features of gamma chain deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sandhoff disease v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinoblastoma v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary alveolar microlithiasis v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PTEN Hamartoma Tumor Syndrome v1.8 | Arina Puzriakova Panel version 1.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pseudoxanthoma elasticum v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary hyperaldosteronism v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| POLG-related disorder v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenylketonuria v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Peutz Jeghers Syndrome v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nijmegen breakage syndrome v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Niemann-Pick disease type A or B v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Niemann Pick disease type C v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neutropaenia consistent with ELANE variants v1.7 | Arina Puzriakova Panel version 1.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neuronal ceroid lipofuscinosis type 2 v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurofibromatosis type 1 (GMS) v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes - small panel v1.8 | Arina Puzriakova Panel version 1.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| NARP syndrome or maternally inherited Leigh syndrome v2.4 | Arina Puzriakova Panel version 2.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Multiple exostoses v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Multiple endocrine neoplasia type 2 v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mucopolysaccharidosis type VI v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mucopolysaccharidosis type IVA v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mucopolysaccharidosis type IIIB v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mucopolysaccharidosis type IIIA v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mucopolysaccharidosis type II v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mucopolysaccharidosis type IH or S v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mucolipidosis II and III Alpha or Beta v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monitoring for G(M)CSF escape variants v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial neurogastrointestinal encephalopathy v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial Complex V deficiency, TMEM70 type v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lysosomal acid lipase deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lymphoproliferative syndrome with absent SAP expression v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Krabbe disease - Saposin A deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Krabbe disease - GALC deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited parathyroid cancer v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Incontinentia pigmenti v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary angioedema types I and II v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Haemophagocytic syndrome with absent XIAP expression v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Haemophagocytic syndrome with absent perforin expression v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Glycogen storage disease V v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Glucokinase-related fasting hyperglycaemia v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Generalised arterial calcification in infancy v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gaucher disease v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fumarate hydratase-related tumour syndromes v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial tumours of the nervous system v3.3 | Arina Puzriakova Panel version 3.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial dysalbuminaemic hyperthyroxinaemia v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Factor XIII deficiency v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Factor XI deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Factor X deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Factor VIII deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Factor VII deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Factor V deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Factor IX deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Factor II deficiency v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Facioscapulohumeral muscular dystrophy - extended testing v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fabry disease v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Elastin-related phenotypes v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Duchenne or Becker muscular dystrophy v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DICER1-related cancer predisposition v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystinosis v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic fibrosis - Diagnostic v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital adrenal hyperplasia v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Combined vitamin K-dependent clotting factor deficiency v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Central congenital hypoventilation v1.9 | Arina Puzriakova Panel version 1.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Carney complex v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Calcium-sensing receptor phenotypes v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CADASIL v1.9 | Arina Puzriakova Panel version 1.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Blepharophimosis ptosis and epicanthus inversus v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Beckwith-Wiedemann syndrome v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Barth syndrome v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary isolated diabetes insipidus v2.4 | Arina Puzriakova Panel version 2.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited prostate cancer v1.8 | Arina Puzriakova Panel version 1.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Li Fraumeni Syndrome v1.8 | Arina Puzriakova Panel version 1.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary diffuse gastric cancer v2.7 | Arina Puzriakova Panel version 2.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric pseudo-obstruction syndrome v2.8 | Arina Puzriakova Panel version 2.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BAP1 associated tumour predisposition syndrome v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoimmune Polyendocrine Syndrome v1.6 | Arina Puzriakova Panel version 1.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoimmune lymphoproliferative syndrome with defective apoptosis v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia telangiectasia - mutation testing v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| APC associated Polyposis v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alveolar capillary dysplasia with misalignment of pulmonary veins v1.10 | Arina Puzriakova Panel version 1.9 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alstrom syndrome v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v2.1 | Arina Puzriakova Panel version 2.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v2.0 | Arina Puzriakova promoted panel to version 2.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agammaglobulinaemia with absent BTK expression v1.5 | Arina Puzriakova Panel version 1.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute intermittent porphyria v2.3 | Arina Puzriakova Panel version 2.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.18 | Arina Puzriakova Panel version 1.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v3.1 | Arina Puzriakova Panel version 3.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v3.0 | Arina Puzriakova promoted panel to version 3.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Multi Locus Imprinting Disorder (MLID) v2.5 | Arina Puzriakova Panel version 2.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malignant hyperthermia v1.7 | Arina Puzriakova Panel version 1.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.17 | Arina Puzriakova Panel version 3.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thrombocythaemia v2.3 | Arina Puzriakova Panel version 2.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteopetrosis v2.3 | Arina Puzriakova Panel version 2.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.14 | Arina Puzriakova Panel version 8.13 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.31 | Arina Puzriakova Panel version 8.30 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cardiac arrhythmias - additional genes v3.13 | Arina Puzriakova Panel version 3.12 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypercholesterolaemia (GMS) v2.7 | Arina Puzriakova Panel version 2.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v8.5 | Arina Puzriakova Panel version 8.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurological segmental overgrowth v3.6 | Arina Puzriakova Panel version 3.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal ciliopathies v7.2 | Arina Puzriakova Panel version 7.1 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal ciliopathies v5.2 | Arina Puzriakova Panel version 5.1 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurological ciliopathies v7.2 | Arina Puzriakova Panel version 7.1 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ophthalmological ciliopathies v6.2 | Arina Puzriakova Panel version 6.1 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thoracic aortic aneurysm or dissection (GMS) v5.8 | Arina Puzriakova Panel version 5.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Corneal dystrophy v4.12 | Arina Puzriakova Panel version 4.11 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Polycystic liver disease v1.34 | Arina Puzriakova Panel version 1.33 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated and arrhythmogenic cardiomyopathy v4.4 | Arina Puzriakova Panel version 4.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.4 | Arina Puzriakova Panel version 5.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited phaeochromocytoma and paraganglioma excluding NF1 v5.1 | Arina Puzriakova Panel version 5.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited phaeochromocytoma and paraganglioma excluding NF1 v5.0 | Arina Puzriakova promoted panel to version 5.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Endocrine neoplasia v3.9 | Arina Puzriakova Panel version 3.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited breast cancer and ovarian cancer v3.3 | Arina Puzriakova Panel version 3.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.9 | Arina Puzriakova Panel version 7.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.8 | Arina Puzriakova Panel version 9.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, adult onset v6.14 | Arina Puzriakova Panel version 6.13 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary pigmented nodular adrenocortical disease v1.13 | Arina Puzriakova Panel version 1.12 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.26 | Arina Puzriakova Panel version 4.25 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mosaic skin disorders - Deep sequencing v4.1 | Arina Puzriakova Panel version 4.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mosaic skin disorders - Deep sequencing v4.0 | Arina Puzriakova promoted panel to version 4.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Vascular skin disorders v2.8 | Arina Puzriakova Panel version 2.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Epidermodysplasia verruciformis v1.9 | Arina Puzriakova Panel version 1.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cutaneous photosensitivity with a likely genetic cause v3.18 | Arina Puzriakova Panel version 3.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.13 | Arina Puzriakova Panel version 5.12 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Multiple monogenic benign skin tumours v2.8 | Arina Puzriakova Panel version 2.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autosomal recessive primary hypertrophic osteoarthropathy v2.3 | Arina Puzriakova Panel version 2.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Palmoplantar keratodermas v4.17 | Arina Puzriakova Panel version 4.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.17 | Arina Puzriakova Panel version 4.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Epidermolysis bullosa and congenital skin fragility v2.17 | Arina Puzriakova Panel version 2.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.5 | Arina Puzriakova Panel version 5.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial tumoral calcinosis v1.13 | Arina Puzriakova Panel version 1.12 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Respiratory ciliopathies including non-CF bronchiectasis v5.4 | Arina Puzriakova Panel version 5.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Laterality disorders and isomerism v5.3 | Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tubulointerstitial kidney disease v3.35 | Arina Puzriakova Panel version 3.34 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe insulin resistance and lipodystrophy syndromes v5.3 | Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bleeding and platelet disorders v4.17 | Arina Puzriakova Panel version 4.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.18 | Arina Puzriakova Panel version 4.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bardet Biedl syndrome v2.19 | Arina Puzriakova Panel version 2.18 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal muscle channelopathy v3.10 | Arina Puzriakova Panel version 3.9 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.7 | Arina Puzriakova Panel version 4.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.8 | Arina Puzriakova Panel version 6.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.18 | Arina Puzriakova Panel version 5.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex V deficiency v3.7 | Arina Puzriakova Panel version 3.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex IV deficiency v5.5 | Arina Puzriakova Panel version 5.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.9 | Arina Puzriakova Panel version 2.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex II deficiency v2.13 | Arina Puzriakova Panel version 2.12 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex I deficiency v4.3 | Arina Puzriakova Panel version 4.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial DNA maintenance disorder v3.11 | Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial liver disease v1.17 | Arina Puzriakova Panel version 1.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pyruvate dehydrogenase (PDH) deficiency v1.42 | Arina Puzriakova Panel version 1.41 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lysosomal storage disorder v3.11 | Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Glycogen storage disease v2.9 | Arina Puzriakova Panel version 2.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial Chylomicronaemia Syndrome v3.7 | Arina Puzriakova Panel version 3.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neuronal ceroid lipofuscinosis v3.5 | Arina Puzriakova Panel version 3.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to acute myeloid leukaemia (AML) v3.11 | Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited pancreatic cancer v3.5 | Arina Puzriakova Panel version 3.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited predisposition to GIST v1.18 | Arina Puzriakova Panel version 1.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial melanoma v2.16 | Arina Puzriakova Panel version 2.15 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited renal cancer v1.31 | Arina Puzriakova Panel version 1.30 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytopenia - NOT Fanconi anaemia v5.8 | Arina Puzriakova Panel version 5.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare anaemia v4.8 | Arina Puzriakova Panel version 4.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Combined factor V and VIII deficiency v1.13 | Arina Puzriakova Panel version 1.12 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thrombophilia with a likely monogenic cause v3.3 | Arina Puzriakova Panel version 3.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Iron metabolism disorders - NOT common HFE mutations v4.4 | Arina Puzriakova Panel version 4.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intestinal failure or congenital diarrhoea v3.18 | Arina Puzriakova Panel version 3.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.1 | Arina Puzriakova Panel version 2.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Non-acute porphyrias v2.0 | Arina Puzriakova promoted panel to version 2.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.8 | Arina Puzriakova Panel version 2.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Albinism or congenital nystagmus v4.13 | Arina Puzriakova Panel version 4.12 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sporadic aniridia v3.8 | Arina Puzriakova Panel version 3.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Structural eye disease v5.8 | Arina Puzriakova Panel version 5.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fanconi anaemia or Bloom syndrome v2.18 | Arina Puzriakova Panel version 2.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Common craniosynostosis syndromes v1.19 | Arina Puzriakova Panel version 1.18 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Progressive cardiac conduction disease v2.18 | Arina Puzriakova Panel version 2.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited polyposis and early onset colorectal cancer - germline testing v4.3 | Arina Puzriakova Panel version 4.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited MMR deficiency (Lynch syndrome) v1.16 | Arina Puzriakova Panel version 1.15 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary systemic amyloidosis v1.31 | Arina Puzriakova Panel version 1.30 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.1 | Arina Puzriakova Panel version 8.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DDG2P v8.0 | Arina Puzriakova promoted panel to version 8.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pituitary hormone deficiency v4.11 | Arina Puzriakova Panel version 4.10 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypophosphataemia or rickets v4.5 | Arina Puzriakova Panel version 4.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.11 | Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v8.9 | Arina Puzriakova Panel version 8.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.1 | Arina Puzriakova Panel version 8.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v8.0 | Arina Puzriakova promoted panel to version 8.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.23 | Arina Puzriakova Panel version 9.22 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.7 | Arina Puzriakova Panel version 8.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.5 | Arina Puzriakova Panel version 9.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic diabetes v3.27 | Arina Puzriakova Panel version 3.26 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.30 | Arina Puzriakova Panel version 9.29 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.5 | Arina Puzriakova Panel version 9.4 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.57 | Arina Puzriakova Panel version 9.56 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.92 | Arina Puzriakova Panel version 9.91 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pancreatitis v3.7 | Arina Puzriakova Panel version 3.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.1 | Arina Puzriakova Panel version 9.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v9.0 | Arina Puzriakova promoted panel to version 9.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.7 | Arina Puzriakova Panel version 3.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.1 | Arina Puzriakova Panel version 10.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v10.0 | Arina Puzriakova promoted panel to version 10.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital hyperinsulinism v3.10 | Arina Puzriakova Panel version 3.9 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.15 | Arina Puzriakova Panel version 9.14 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neonatal diabetes v6.3 | Arina Puzriakova Panel version 6.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal tubulopathies v6.10 | Arina Puzriakova Panel version 6.9 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cystic kidney disease v9.2 | Arina Puzriakova Panel version 9.1 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Amelogenesis imperfecta v4.38 | Arina Puzriakova Panel version 4.37 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.17 | Arina Puzriakova Panel version 10.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hyperthyroidism v3.8 | Arina Puzriakova Panel version 3.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Distal myopathies v7.6 | Arina Puzriakova Panel version 7.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myaesthenic syndrome v6.3 | Arina Puzriakova Panel version 6.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.6 | Arina Puzriakova Panel version 8.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital myopathy v7.78 | Arina Puzriakova Panel version 7.77 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Short QT syndrome v3.24 | Arina Puzriakova Panel version 3.23 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Catecholaminergic polymorphic VT v5.6 | Arina Puzriakova Panel version 5.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital muscular dystrophy v7.27 | Arina Puzriakova Panel version 7.26 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Osteogenesis imperfecta v6.8 | Arina Puzriakova Panel version 6.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary arterial hypertension v4.15 | Arina Puzriakova Panel version 4.14 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.47 | Arina Puzriakova Panel version 6.46 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.18 | Arina Puzriakova Panel version 6.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.15 | Arina Puzriakova Panel version 5.14 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v7.1 | Arina Puzriakova Panel version 7.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v7.0 | Arina Puzriakova promoted panel to version 7.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.14 | Arina Puzriakova Panel version 9.13 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Erythrocytosis v3.3 | Arina Puzriakova Panel version 3.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nephrocalcinosis or nephrolithiasis v6.3 | Arina Puzriakova Panel version 6.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cerebral vascular malformations v5.3 | Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital adrenal hypoplasia v5.6 | Arina Puzriakova Panel version 5.5 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited ovarian cancer (without breast cancer) v5.3 | Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Atypical haemolytic uraemic syndrome v3.11 | Arina Puzriakova Panel version 3.10 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arrhythmogenic right ventricular cardiomyopathy v3.18 | Arina Puzriakova Panel version 3.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe early-onset obesity v7.1 | Arina Puzriakova Panel version 7.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe early-onset obesity v7.0 | Arina Puzriakova promoted panel to version 7.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.35 | Arina Puzriakova Panel version 6.34 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary haemorrhagic telangiectasia v3.9 | Arina Puzriakova Panel version 3.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.19 | Arina Puzriakova Panel version 10.18 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.14 | Arina Puzriakova Panel version 6.13 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pneumothorax - familial v3.8 | Arina Puzriakova Panel version 3.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Haematuria v2.20 | Arina Puzriakova Panel version 2.19 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Segmental overgrowth disorders - Deep sequencing v5.3 | Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Malformations of cortical development v8.7 | Arina Puzriakova Panel version 8.6 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.15 | Arina Puzriakova Panel version 3.14 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.9 | Arina Puzriakova Panel version 7.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric motor neuronopathies v3.17 | Arina Puzriakova Panel version 3.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holoprosencephaly v6.4 | Arina Puzriakova Panel version 6.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.9 | Arina Puzriakova Panel version 3.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Long QT syndrome v3.15 | Arina Puzriakova Panel version 3.14 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.9 | Arina Puzriakova Panel version 6.8 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary lymphoedema v5.3 | Arina Puzriakova Panel version 5.2 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.17 | Arina Puzriakova Panel version 4.16 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypertrophic cardiomyopathy v6.4 | Arina Puzriakova Panel version 6.3 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital hypothyroidism v4.1 | Arina Puzriakova Panel version 4.0 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital hypothyroidism v4.0 | Arina Puzriakova promoted panel to version 4.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.8 | Arina Puzriakova Panel version 8.7 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Brugada syndrome and cardiac sodium channel disease v3.18 | Arina Puzriakova Panel version 3.17 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.23 | Arina Puzriakova Panel version 4.22 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Stickler syndrome v4.12 | Arina Puzriakova Panel version 4.11 has been signed off on 2026-08-12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.98 | Arina Puzriakova List of related panels changed from Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; Intellectual disability - microarray and sequencing; R29 to Coarse facial features including Coffin-Siris-like disorders; ID; Moderate; severe or profound intellectual disability; Schizophrenia plus additional features; Intellectual disability - microarray; fragile X and sequencing; Intellectual disability - microarray and sequencing | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mosaic skin disorders - Deep sequencing v3.35 | Arina Puzriakova Panel name changed from Mosaic skin disorders - deep sequencing to Mosaic skin disorders - Deep sequencing | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monitoring for G(M)CSF escape variants v1.5 |
Arina Puzriakova Panel name changed from Monitoring for G(M)CSF escape mutations to Monitoring for G(M)CSF escape variants List of related panels changed from R338; GT188; TP539 to Monitoring for G(M)CSF escape mutations; R338; GT188; TP539 |
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| Mitochondrial liver disease v1.16 |
Arina Puzriakova Panel name changed from Mitochondrial liver disease, including transient infantile liver failure to Mitochondrial liver disease List of related panels changed from Mitochondrial liver disease; R317; GT766; TP167 to Mitochondrial liver disease; including transient infantile liver failure; R317; GT766; TP167 |
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| Cystic fibrosis - Diagnostic v1.5 |
Achchuthan Shanmugasundram Panel name changed from Cystic fibrosis diagnostic test to Cystic fibrosis - Diagnostic List of related panels changed from R184; GT219; TP46 to Cystic fibrosis diagnostic test; R184; GT219; TP46 |
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| Congenital adrenal hyperplasia v1.5 |
Achchuthan Shanmugasundram Panel name changed from Congenital adrenal hyperplasia diagnostic test to Congenital adrenal hyperplasia List of related panels changed from R180; GT724; TP41 to Congenital adrenal hyperplasia diagnostic test; R180; GT724; TP41 |
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| Fanconi anaemia or Bloom syndrome v2.17 |
Achchuthan Shanmugasundram Panel name changed from Confirmed Fanconi anaemia or Bloom syndrome to Fanconi anaemia or Bloom syndrome List of related panels changed from R229; R258; Confirmed Fanconi anaemia or Bloom syndrome - mutation testing; Cytopenia - Fanconi breakage testing indicated; GT566; TP191 to Confirmed Fanconi anaemia or Bloom syndrome - mutation testing; Cytopenia - Fanconi breakage testing indicated; Confirmed Fanconi anaemia or Bloom syndrome; R229; R258; GT566; TP191 |
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| Leukodystrophy, childhood onset v31.151 |
Achchuthan Shanmugasundram Panel name changed from Childhood onset leukodystrophy to Leukodystrophy, childhood onset List of related panels changed from White matter disorders - childhood onset; R109; GT207; TP419 to White matter disorders - childhood onset; Childhood onset leukodystrophy; R109; GT207; TP419 |
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| Hereditary ataxia, adult onset v9.4 |
Arina Puzriakova Panel name changed from Hereditary ataxia with onset in adulthood to Hereditary ataxia, adult onset List of related panels changed from Hereditary ataxia - adult onset to Hereditary ataxia with onset in adulthood; Hereditary ataxia - adult onset |
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| Hereditary spastic paraplegia, childhood onset v9.7 |
Achchuthan Shanmugasundram Panel name changed from Childhood onset hereditary spastic paraplegia to Hereditary spastic paraplegia, childhood onset List of related panels changed from Hereditary spastic paraplegia - childhood onset; R61; GT34; TP579 to Hereditary spastic paraplegia - childhood onset; Childhood onset hereditary spastic paraplegia; R61; GT34; TP579 |
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| Hereditary ataxia and cerebellar anomalies, childhood onset v23.31 |
Arina Puzriakova Panel name changed from Hereditary ataxia and cerebellar anomalies - childhood onset to Hereditary ataxia and cerebellar anomalies, childhood onset List of related panels changed from Hereditary ataxia with onset in childhood; Cerebellar anomalies; R55; R84; GT936; TP356; TP411 to Hereditary ataxia and cerebellar anomalies - childhood onset; Hereditary ataxia with onset in childhood; Cerebellar anomalies; R55; R84; GT936; TP356; TP411 |
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| Familial hyperparathyroidism or Hypocalciuric hypercalcaemia v3.10 | Arina Puzriakova Panel name changed from Familial hyperparathyroidism or hypocalciuric hypercalcaemia to Familial hyperparathyroidism or Hypocalciuric hypercalcaemia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| White matter disorders and cerebral calcification - childhood onset v8.6 |
Ida Ertmanska Panel name changed from White matter disorders and cerebral calcification - narrow panel to White matter disorders and cerebral calcification - childhood onset List of related panels changed from to White matter disorders and cerebral calcification - narrow panel |
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| Dystonia, chorea or related movement disorder, childhood onset v8.13 |
Achchuthan Shanmugasundram Panel name changed from Childhood onset dystonia, chorea or related movement disorder to Dystonia, chorea or related movement disorder, childhood onset List of related panels changed from Childhood onset dystonia or chorea or related movement disorder; R57; GT25; TP173 to Childhood onset dystonia or chorea or related movement disorder; Childhood onset dystonia; chorea or related movement disorder; R57; GT25; TP173 |
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| Familial Chylomicronaemia Syndrome v3.6 |
Arina Puzriakova Panel name changed from Familial chylomicronaemia syndrome (FCS) to Familial Chylomicronaemia Syndrome List of related panels changed from Lipoprotein lipase deficiency; R324; GT850; TP33 to Familial chylomicronaemia syndrome (FCS); Lipoprotein lipase deficiency; R324; GT850; TP33 |
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| Spinal muscular atrophy - Diagnostic v1.5 |
Ida Ertmanska Panel name changed from Spinal muscular atrophy type 1 rare mutation testing to Spinal muscular atrophy - Diagnostic List of related panels changed from R71; GT571; TP137 to Spinal muscular atrophy type 1 rare mutation testing; R71; GT571; TP137 |
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| Ataxia and cerebellar anomalies - childhood onset v9.22 |
Achchuthan Shanmugasundram Panel name changed from Ataxia and cerebellar anomalies - narrow panel to Ataxia and cerebellar anomalies - childhood onset List of related panels changed from to Ataxia and cerebellar anomalies - narrow panel |
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| Leukodystrophy, adult onset v7.8 |
Achchuthan Shanmugasundram Panel name changed from Adult onset leukodystrophy to Leukodystrophy, adult onset List of related panels changed from White matter disorders - adult onset; R62; GT117; TP85 to White matter disorders - adult onset; Adult onset leukodystrophy; R62; GT117; TP85 |
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| Neurodegenerative disorders, adult onset v9.4 |
Achchuthan Shanmugasundram Panel name changed from Adult onset neurodegenerative disorder to Neurodegenerative disorders, adult onset List of related panels changed from Neurodegenerative disorders - adult onset; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy; R58 to Neurodegenerative disorders - adult onset; Adult onset neurodegenerative disorder; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy |
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| Early onset or syndromic epilepsy v9.56 | Arina Puzriakova List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; Genetic epilepsy syndromes; R59 to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; Genetic epilepsy syndromes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sickle cell, thalassaemia and other haemoglobinopathies v2.11 | Ida Ertmanska List of related panels changed from R93; Thalassaemia and other haemoglobinopathies; GT713; TP199; TP473 to Sickle cell; thalassaemia and other haemoglobinopathies; R93; Sickle cell; thalassaemia and other haemoglobinopathies trait or carrier testing; R361; GT713; TP199; TP473 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.17 |
Ida Ertmanska Panel name changed from Pulmonary fibrosis familial to Pulmonary Fibrosis, Familial List of related panels changed from R421; GT1047; TP235 to Pulmonary fibrosis familial; R421; GT1047; TP235 |
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| Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Diagnostic v1.4 |
Arina Puzriakova Panel name changed from Diagnostic testing for MCADD - Medium-chain acyl-CoA dehydrogenase deficiency - full ACADM sequencing to Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) - Diagnostic List of related panels changed from R451; GT1105; TP378 to Diagnostic testing for MCADD - Medium-chain acyl-CoA dehydrogenase deficiency - full ACADM sequencing; R451; GT1105; TP378 |
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| PTEN Hamartoma Tumor Syndrome v1.7 |
Ida Ertmanska Panel name changed from PTEN Hamartoma Tumour Syndrome to PTEN Hamartoma Tumor Syndrome List of related panels changed from PTEN Hamartoma Tumor Syndrome; R213; GT1202; TP66 to PTEN Hamartoma Tumour Syndrome; R213; GT1202; TP66 |
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| Primary hyperaldosteronism v1.5 |
Ida Ertmanska Panel name changed from Primary hyperaldosteronism - KCNJ5 to Primary hyperaldosteronism List of related panels changed from R344; GT176; TP410 to Primary hyperaldosteronism - KCNJ5; R344; GT176; TP410 |
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| Isovaleric acidaemia - Diagnostic v1.4 |
Arina Puzriakova Panel name changed from Diagnostic testing for Isovaleric acidaemia to Isovaleric acidaemia - Diagnostic List of related panels changed from R450; GT1229; TP67 to Diagnostic testing for Isovaleric acidaemia; R450; GT1229; TP67 |
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| Multi Locus Imprinting Disorder (MLID) v2.4 | Ida Ertmanska List of related panels changed from R417.2; GT377; TP270; Multi locus imprinting disorders to Multi locus imprinting disorders; R417.2; GT377; TP270 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neutropaenia consistent with ELANE variants v1.6 | Ida Ertmanska List of related panels changed from R313; GT502; TP76; Neutropaenia consistent with ELANE mutations to Neutropaenia consistent with ELANE mutations; R313; GT502; TP76 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Glutaric acidaemia type 1 - Diagnostic v1.5 |
Arina Puzriakova Panel name changed from Diagnostic testing for Glutaric acidaemia I to Glutaric acidaemia type 1 - Diagnostic List of related panels changed from R449; GT374; TP407 to Diagnostic testing for Glutaric acidaemia I; R449; GT374; TP407 |
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| Possible mitochondrial disorder, nuclear genes v5.17 | Ida Ertmanska Panel name changed from Possible mitochondrial disorder - nuclear genes to Possible mitochondrial disorder, nuclear genes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, adult onset v6.13 |
Achchuthan Shanmugasundram Panel name changed from Adult onset hereditary spastic paraplegia to Hereditary spastic paraplegia, adult onset List of related panels changed from Hereditary spastic paraplegia - adult onset to Hereditary spastic paraplegia - adult onset; Adult onset hereditary spastic paraplegia |
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| Possible mitochondrial disorder, nuclear genes v5.16 | Ida Ertmanska List of related panels changed from R63; GT759; TP627 to Possible mitochondrial disorder - nuclear genes; R63; GT759; TP627 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neutropaenia consistent with ELANE variants v1.5 |
Ida Ertmanska Panel name changed from Neutropaenia consistent with ELANE mutations to Neutropaenia consistent with ELANE variants List of related panels changed from R313; GT502; TP76 to R313; GT502; TP76; Neutropaenia consistent with ELANE mutations |
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| Dystonia, chorea or related movement disorder, adult onset v6.7 |
Achchuthan Shanmugasundram Panel name changed from Adult onset dystonia, chorea or related movement disorder to Dystonia, chorea or related movement disorder, adult onset List of related panels changed from Adult onset movement disorder to Adult onset movement disorder; Adult onset dystonia; chorea or related movement disorder |
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| Multi Locus Imprinting Disorder (MLID) v2.3 |
Ida Ertmanska Panel name changed from Multi locus imprinting disorders to Multi Locus Imprinting Disorder (MLID) List of related panels changed from R417.2; GT377; TP270 to R417.2; GT377; TP270; Multi locus imprinting disorders |
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| Mitochondrial disorders v10.18 | UQCC1 | Hannah Robinson reviewed gene: UQCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39504961; Phenotypes: lactic acidosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.15 | UQCC1 | Hannah Robinson reviewed gene: UQCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39504961; Phenotypes: lactic acidosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorder with complex III deficiency v2.8 | UQCC1 | Hannah Robinson reviewed gene: UQCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39504961; Phenotypes: lactic acidosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.6 | ATP1A3 |
Katherine Schon gene: ATP1A3 was added gene: ATP1A3 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature Mode of inheritance for gene: ATP1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP1A3 were set to PMID: 37043503 Phenotypes for gene: ATP1A3 were set to spasticity; developmental delay; intellectual disability Penetrance for gene: ATP1A3 were set to Complete Review for gene: ATP1A3 was set to GREEN Added comment: Recurrent de novo pathogenic variant reported in nine individuals with childhood onset of phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Sources: Literature |
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| Paediatric pseudo-obstruction syndrome v2.7 | MT-TL1 |
Katherine Schon gene: MT-TL1 was added gene: MT-TL1 was added to Paediatric pseudo-obstruction syndrome. Sources: Literature Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL Publications for gene: MT-TL1 were set to PMID: 27453452; 42024134; 28458318 Phenotypes for gene: MT-TL1 were set to Intestinal pseudo-obstruction HP:0004389 Penetrance for gene: MT-TL1 were set to Incomplete Mode of pathogenicity for gene: MT-TL1 was set to Other Review for gene: MT-TL1 was set to GREEN Added comment: Intestinal pseudo-obstruction is observed as one of the phenotypes of the multi-system mitochondrial disease associated with the m.3243A>G pathogenic variant. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.91 | PTPN6 | Achchuthan Shanmugasundram Classified gene: PTPN6 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.91 | PTPN6 | Achchuthan Shanmugasundram Gene: ptpn6 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.90 | PTPN6 | Achchuthan Shanmugasundram Publications for gene: PTPN6 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 | PTPN6 | Achchuthan Shanmugasundram edited their review of gene: PTPN6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 | PTPN6 | Achchuthan Shanmugasundram edited their review of gene: PTPN6: Changed publications to: 21406173 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 | PTPN6 | Achchuthan Shanmugasundram reviewed gene: PTPN6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 | GPR15 | Achchuthan Shanmugasundram Classified gene: GPR15 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 | GPR15 |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with GPR15 variants and with early-onset inflammatory bowel disease. Patients were reported with both biallelic and monoallelic inheritance in at least two families each - biallelic in families 1-3 and monoallelic carriers in families 2 and 4. However, the phenotype is milder in monoallelic carriers. There is also functional evidence available from both homozygous and heterozygous varaiants and from GPR15 knockout model. Hence, this gene should be promoted to green rating with 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' MOI in the next GMS update. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.89 | GPR15 | Achchuthan Shanmugasundram Gene: gpr15 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.88 | GPR15 | Achchuthan Shanmugasundram Phenotypes for gene: GPR15 were changed from Inflammatory bowel disease; IBD; VEOIBD to inflammatory bowel disease, MONDO:0005265 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.87 | GPR15 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: GPR15. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.87 | GPR15 | Achchuthan Shanmugasundram reviewed gene: GPR15: Rating: GREEN; Mode of pathogenicity: None; Publications: 42259915; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.97 | ZBTB7B | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: The global developmental delay is reported only as a clinical feature of the broader syndrome, without formal cognitive/IQ assessment in the single reported case. No functional or mechanistic evidence specifically supports a causal role for ZBTB7B in intellectual disability. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: Global developmental delay is reported only as a clinical feature of the broader syndrome, without formal cognitive/IQ assessment in the single reported case. No functional or mechanistic evidence specifically supports a causal role for ZBTB7B in intellectual disability. Hence, this gene should be rated red with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.97 | ZBTB7B | Achchuthan Shanmugasundram Classified gene: ZBTB7B as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.97 | ZBTB7B | Achchuthan Shanmugasundram Added comment: Comment on list classification: The global developmental delay is reported only as a clinical feature of the broader syndrome, without formal cognitive/IQ assessment in the single reported case. No functional or mechanistic evidence specifically supports a causal role for ZBTB7B in intellectual disability. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.97 | ZBTB7B | Achchuthan Shanmugasundram Gene: zbtb7b has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.9 | ZBTB7B | Achchuthan Shanmugasundram Phenotypes for gene: ZBTB7B were changed from inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925 to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925; Global developmental delay, HP:0001263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.8 | ZBTB7B | Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed phenotypes to: inborn error of immunity, MONDO:0003778, interstitial lung disease, MONDO:0015925, Global developmental delay, HP:0001263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.87 | ZBTB7B | Achchuthan Shanmugasundram Phenotypes for gene: ZBTB7B were changed from inborn error of immunity, MONDO:0003778 to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925; Global developmental delay, HP:0001263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 | ZBTB7B | Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed phenotypes to: inborn error of immunity, MONDO:0003778, interstitial lung disease, MONDO:0015925, Global developmental delay, HP:0001263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.8 | ZBTB7B |
Achchuthan Shanmugasundram changed review comment from: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay. Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype. Sources: Literature; to: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay. Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 07 August 2026). Sources: Literature |
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| Intellectual disability v10.96 | ZBTB7B |
Achchuthan Shanmugasundram gene: ZBTB7B was added gene: ZBTB7B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZBTB7B were set to 40392549 Phenotypes for gene: ZBTB7B were set to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925; Global developmental delay, HP:0001263 Review for gene: ZBTB7B was set to RED Added comment: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with global developmental delay and growth failure, alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, fibroinflammatory interstitial lung disease, corneal defects, and sensorineural hearing loss. Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets; however, all functional validation (lentiviral gene-transfer in healthy-donor T cells and pulmonary fibroblasts, luciferase, EMSA, HT-SELEX, ChIP-seq) was directed at immune and fibrotic mechanisms, with no neuronal/CNS cell model or evidence directly linking K360N to a neurodevelopmental mechanism. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 07 August 2026). Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v9.21 | GPN2 | Ida Ertmanska Classified gene: GPN2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.21 | GPN2 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there are now 2 pedigrees reported where individuals harbouring biallelic GPN2 variants presented with ataxia (2 sibs, age of onset not specified), and cerebellar atrophy (both families). Based on available evidence, this gene can only be rated Amber. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.21 | GPN2 | Ida Ertmanska Gene: gpn2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.95 | COPB1 | Luke Stuart reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33632302, 40396222; Phenotypes: Baralle-Macken syndrome (OMIM #619255), accessed 08/2026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.34 | GPN2 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: GPN2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.34 | GPN2 | Ida Ertmanska Classified gene: GPN2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.34 | GPN2 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there are now 3 families (2 with shared ancestry) where individuals harbouring biallelic GPN2 variants presented with hearing loss. In addition, there is some supportive functional evidence. Hence, this gene can be promoted to Green on Monogenic hearing loss. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.34 | GPN2 | Ida Ertmanska Gene: gpn2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.13 | COPB1 | Luke Stuart reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33632302, 40396222; Phenotypes: Baralle-Macken syndrome (OMIM #619255), accessed 08/2026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.95 | GPN2 | Ida Ertmanska Classified gene: GPN2 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.95 | GPN2 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there is only 1 individual reported with biallelic GPN2 variants and mild intellectual disability. Hence, this gene can only be rated Red with the current level of evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.95 | GPN2 | Ida Ertmanska Gene: gpn2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bilateral congenital or childhood onset cataracts v8.5 | COPB1 | Luke Stuart reviewed gene: COPB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33632302, 40396222; Phenotypes: Baralle-Macken syndrome (OMIM #619255, accessed 08/2026); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.8 | ZBTB7B | Achchuthan Shanmugasundram Classified gene: ZBTB7B as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.8 | ZBTB7B | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one case with a syndromic phenotype including fibroinflammatory interstitial lung disease and functional evidence reported in support of the association of ZBTB7B gene with this panel. Hence, this gene can be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.8 | ZBTB7B | Achchuthan Shanmugasundram Gene: zbtb7b has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.7 | ZBTB7B |
Achchuthan Shanmugasundram changed review comment from: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay. Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype. This is currently a single reported case, and ILD occurs as one component of a broader multisystem syndrome rather than an isolated pulmonary phenotype, which should be considered when applying this gene to an ILD-specific panel. Sources: Literature; to: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay. Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype. Sources: Literature |
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| Childhood interstitial lung disease v1.7 | ZBTB7B | Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood interstitial lung disease v1.7 | ZBTB7B |
Achchuthan Shanmugasundram gene: ZBTB7B was added gene: ZBTB7B was added to Childhood interstitial lung disease. Sources: Literature Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZBTB7B were set to 40392549 Phenotypes for gene: ZBTB7B were set to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925 Review for gene: ZBTB7B was set to RED Added comment: PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/allergic/fibrotic syndrome, identified with a de novo heterozygous missense variant (c.1080A>C/p.Lys360Asn) by trio whole-genome sequencing. The patient presented with severe fibroinflammatory interstitial lung disease (pulmonary lipoproteinosis with subpleural cystic/honeycomb remodeling on lung biopsy at 3.75 years), alongside CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, corneal defects, sensorineural hearing loss, and global developmental delay. Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. Lung-specific causal evidence came from lentiviral gene-transfer of K360N into healthy-donor pulmonary fibroblasts, which reproduced a profibrotic gene signature (including increased COL2A1 expression), supporting a cell-intrinsic mechanism for fibrosis independent of the immune phenotype. This is currently a single reported case, and ILD occurs as one component of a broader multisystem syndrome rather than an isolated pulmonary phenotype, which should be considered when applying this gene to an ILD-specific panel. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 | KARS | Ida Ertmanska commented on gene: KARS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 | KARS | Ida Ertmanska Tag new-gene-name tag was added to gene: KARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 | ZBTB7B | Achchuthan Shanmugasundram Classified gene: ZBTB7B as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 | ZBTB7B | Achchuthan Shanmugasundram Added comment: Comment on list classification: A single patient case and functional evidence available in support of the association of ZBTB7B gene with inborn error of immunity. Hence, this gene should be rated amber with the current evidence on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 | ZBTB7B | Achchuthan Shanmugasundram Gene: zbtb7b has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.85 | ZBTB7B | Achchuthan Shanmugasundram Phenotypes for gene: ZBTB7B were changed from CD4+ T-cell deficiency; Allergic disease; Interstitial lung disease; Corneal neovascularization; Corneal scarring; Global developmental delay; Growth failure to inborn error of immunity, MONDO:0003778 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.84 | ZBTB7B | Achchuthan Shanmugasundram Mode of inheritance for gene: ZBTB7B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 | ZBTB7B | Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed phenotypes to: inborn error of immunity, MONDO:0003778 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 | ZBTB7B | Achchuthan Shanmugasundram reviewed gene: ZBTB7B: Rating: AMBER; Mode of pathogenicity: None; Publications: 40392549; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 | SIT1 | Achchuthan Shanmugasundram Classified gene: SIT1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 | SIT1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one case and functional evidence reported in support of the association of SIT1 gene with combined immunodeficiency. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.83 | SIT1 | Achchuthan Shanmugasundram Gene: sit1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.82 | SIT1 | Achchuthan Shanmugasundram Phenotypes for gene: SIT1 were changed from Combined immunodeficiency; Hodgkin lymphoma; Abnormal T cell physiology; Impaired CD8+ T cell cytotoxicity to combined immunodeficiency, MONDO:0015131 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 | SIT1 | Achchuthan Shanmugasundram reviewed gene: SIT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 42128181; Phenotypes: combined immunodeficiency, MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 | SH2B3 | Achchuthan Shanmugasundram Classified gene: SH2B3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 | SH2B3 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are over 10 unrelated patients with biallelic SH2B3 germline variants and with myeloproliferation and autoimmunity. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 | SH2B3 | Achchuthan Shanmugasundram Gene: sh2b3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 | SH2B3 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SH2B3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 | SH2B3 |
Achchuthan Shanmugasundram changed review comment from: PMID:23908464 (2013) reported two siblings from a consanguineous family of Eastern European Ashkenazi Jewish descent presenting with growth retardation, mild developmental delay, chronic hepatitis, and Hashimoto autoimmune thyroiditis. One of them (sister) developed B-precursor acute lymphoblastic leukemia (ALL). They were identified with germline homozygous frameshift variant in SH2B3 gene (c.671insGGCCCCG/ p. Asp231Gly fs*38). PMID:37206266 (2023) reported two further unrelated families with biallelic loss-of-function variants in SH2B3 gene (c.441_468del/ p.Arg148Profs*40 in patient 1 and c.1204G>A/ p.Val402Met in patient 2). These patients showed striking phenotypic similarity to each other as well as to the previous family from PMID:23908464 (2013) - presenting with myeloproliferation and multi-organ autoimmunity. One of these probands also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifested significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. PMID:40481232 (2025) reported ten patients with Germline SH2B3 variants, which included biallelic variants in eight patients (homozygous in seven and compound heterozygous in one) and monoallelic variants in two. However, both patients with germline heterozygous variants had homozygous variants in hematopoietic cells. Of the ten patients, eight (six with biallelic and two with monoallelic germline variants) presented with a myeloproliferative disease characterized by leukocytosis with a leukoerythoblastic picture, low blast percentage in BM and splenomegaly, at birth or in the first months of life. Biallelic variants in this gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 07 August 2026). This gene has been associated with Semidominant inheritance for SH2B3-related immune system disorder (MONDO:1060195) by Childhood, Adolescent and Young Adult Cancer Predisposition GCEP on ClinGen with 'Definitive' rating (https://search.clinicalgenome.org/CCID:009335).; to: PMID:23908464 (2013) reported two siblings from a consanguineous family of Eastern European Ashkenazi Jewish descent presenting with growth retardation, mild developmental delay, chronic hepatitis, and Hashimoto autoimmune thyroiditis. One of them (sister) developed B-precursor acute lymphoblastic leukemia (ALL). They were identified with germline homozygous frameshift variant in SH2B3 gene (c.671insGGCCCCG/ p. Asp231Gly fs*38). PMID:37206266 (2023) reported two further unrelated families with biallelic loss-of-function variants in SH2B3 gene (c.441_468del/ p.Arg148Profs*40 in patient 1 and c.1204G>A/ p.Val402Met in patient 2). These patients showed striking phenotypic similarity to each other as well as to the previous family from PMID:23908464 (2013) - presenting with myeloproliferation and multi-organ autoimmunity. One of these probands also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifested significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. PMID:40481232 (2025) reported ten patients with germline SH2B3 variants, which included biallelic variants in eight patients (homozygous in seven and compound heterozygous in one) and monoallelic variants in two. However, both patients with germline heterozygous variants had homozygous variants in hematopoietic cells. Of the ten patients, eight (six with biallelic and two with monoallelic germline variants) presented with a myeloproliferative disease characterized by leukocytosis with a leukoerythoblastic picture, low blast percentage in BM and splenomegaly, at birth or in the first months of life. Biallelic variants in this gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 07 August 2026). This gene has been associated with Semidominant inheritance for SH2B3-related immune system disorder (MONDO:1060195) by Childhood, Adolescent and Young Adult Cancer Predisposition GCEP on ClinGen with 'Definitive' rating (https://search.clinicalgenome.org/CCID:009335). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 | SH2B3 | Achchuthan Shanmugasundram Publications for gene: SH2B3 were set to 37206266 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.79 | SH2B3 | Achchuthan Shanmugasundram Phenotypes for gene: SH2B3 were changed from Myeloproliferative disorder; Autoimmunity; Hepatosplenomegaly; Thrombosis; Autoimmune thyroiditis; Autoimmune hepatitis; Global developmental delay to SH2B3-related immune system disorder, MONDO:1060195 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 | SH2B3 | Achchuthan Shanmugasundram reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23908464, 37206266, 40481232; Phenotypes: SH2B3-related immune system disorder, MONDO:1060195; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.16 | SHARPIN | Achchuthan Shanmugasundram Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.16 | SHARPIN |
Achchuthan Shanmugasundram gene: SHARPIN was added gene: SHARPIN was added to Autoinflammatory disorders. Sources: Expert Review Amber,Expert list,Literature Q3_26_promote_green tags were added to gene: SHARPIN. Mode of inheritance for gene: SHARPIN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHARPIN were set to 17538631; 38609546 Phenotypes for gene: SHARPIN were set to Autoinflammation with episodic fever and immune dysregulation, OMIM:620795; autoinflammation with episodic fever and immune dysregulation, MONDO:0968982 Penetrance for gene: SHARPIN were set to unknown |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 | SHARPIN | Achchuthan Shanmugasundram Classified gene: SHARPIN as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 | SHARPIN | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients and functional evidence including mouse model available in support of the association of SHARPIN gene with autoinflammatory disease. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 | SHARPIN | Achchuthan Shanmugasundram Gene: sharpin has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.77 | SHARPIN | Achchuthan Shanmugasundram Phenotypes for gene: SHARPIN were changed from Autoinflammation; Immunodeficiency; Recurrent fever; Dermatitis; Recurrent infections to Autoinflammation with episodic fever and immune dysregulation, OMIM:620795; autoinflammation with episodic fever and immune dysregulation, MONDO:0968982 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.76 | SHARPIN | Achchuthan Shanmugasundram Publications for gene: SHARPIN were set to 38609546 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 | SHARPIN | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SHARPIN. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 | SHARPIN | Achchuthan Shanmugasundram reviewed gene: SHARPIN: Rating: GREEN; Mode of pathogenicity: None; Publications: 17538631, 38609546; Phenotypes: Autoinflammation with episodic fever and immune dysregulation, OMIM:620795, autoinflammation with episodic fever and immune dysregulation, MONDO:0968982; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 | Ida Ertmanska changed review comment from: Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating.; to: Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. There are also 4 cases reported with biallelic FBN2 variants and various presentations, none with skeletal manifestations beyond digit anomalies. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 | Ida Ertmanska edited their review of gene: FBN2: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 | Ida Ertmanska Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 | Ida Ertmanska commented on gene: FBN2: Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 | Ida Ertmanska commented on gene: FBN2: Comment on list classification: Heterozygous variants in FBN2 are known to cause congenital contractural arachnodactyly. These patients do not tend to have skeletal defects beyond mild digit anomalies (camptodactyly, arachnodactyly). Tall stature was found to be associated with FBN1, but I did not find evidence of association with FBN2 variants. Hence, this gene should be downgraded to Red on the Skeletal dysplasia panel. An expert-review tag was added as this is a proposed demotion from Green rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 | Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: FBN2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 | Ida Ertmanska Tag Q3_26_demote_red tag was added to gene: FBN2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 |
Ida Ertmanska edited their review of gene: FBN2: Added comment: MONOALLELIC CASES: PMID: 35360850 Sun et al., 2022 Report of 27 congenital contractural arachnodactyly (CCA) patients from 10 families, harbouring heterozygous FBN2 variants (mostly missense, 2 confirmed de novo). Arachnodactyly (27/27, 100%), crumpled ears (26/27, 96.3%), camptodactyly (26/27, 96.3%), and muscle hypoplasia (22/26, 85%) were observed in almost all recruited cases. More than half patients (16/25, 64%) presented with contracture of large joints, including elbow, wrist, knee, ankle, and shoulder. 54% patients (13/24) present with kyphosis or scoliosis; 29% patients (7/24) presented with pectus deformity, including four patients with pectus carinatum and three patients with pectus excavatum; 74% patients (17/23) presented with high arched palate and 71% patients (17/24) presented with micrognathia; 33% patients (9/27) presented with pes planus. No wider skeletal defects noted beyond mild digit anomalies. No patient presented with dolichostenomelia (disproportionately long limbs). PMID: 24833718 Buchan et al., 2014 Study of 852 adolescent idiopathic scoliosis cases and 669 controls. In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10(-4)) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10(-6)) FBN1 variants associated with tall stature - not noted in FBN2.; Changed publications to: 24833718, 25558065, 28383543, 33571691, 35360850, 38791509 |
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| Retinal disorders v9.14 | FBN2 | Ida Ertmanska commented on gene: FBN2: Comment on list classification: As there is only 1 pedigree reported in literature where a het FBN2 variant segregated with macular degeneration, this gene can only be rated Red on Retinal disorders. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.14 | FBN2 |
Ida Ertmanska changed review comment from: PMID: 24899048 Ratnapriya et al., 2014 Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients." A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B). Sources: Literature; to: PMID: 24899048 Ratnapriya et al., 2014 Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients." A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant segregated with disease and was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B). Sources: Literature |
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| Retinal disorders v9.14 | FBN2 |
Ida Ertmanska gene: FBN2 was added gene: FBN2 was added to Retinal disorders. Sources: Literature Mode of inheritance for gene: FBN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBN2 were set to 24899048 Phenotypes for gene: FBN2 were set to Macular degeneration, early-onset, OMIM:616118; macular degeneration, early-onset, MONDO:0014501 Review for gene: FBN2 was set to RED Added comment: PMID: 24899048 Ratnapriya et al., 2014 Summary copied from OMIM: "Reported a family in which a father and 4 sons had early-onset macular dystrophy. Clinical features varied among the 5 affected individuals. The father was diagnosed with macular degeneration at 69 years of age, and examination at age 75 showed large areas of pigment epithelial atrophy in the macula of both eyes. The eldest son reported a history of distorted vision in his left eye from the age of 46 years; examination at age 52 confirmed pigmentary changes of the left macula. Another son had a history of choroidal neovascularization in the right eye at age 35. Two more sons exhibited clinical findings consistent with atrophic macular disease in their forties. There was no history of skeletal, joint, or muscle abnormalities in these patients." A heterozygous FBN2 c.3430G>A, p.Glu1144Lys variant was posed to be causal. MAF in gnomAD v4 = 0.0001761. Conflicting in ClinVar (VUS/B). Sources: Literature |
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| Arthrogryposis v10.16 | FBN2 | Ida Ertmanska Publications for gene: FBN2 were set to 7493032; 33571691; 25558065; 28383543 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | FBN2 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: FBN2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | FBN2 | Ida Ertmanska commented on gene: FBN2: Comment on mode of inheritance: There are 4 unrelated individuals reported in literature with biallelic FBN2 variants. However, these individuals presented with a spectrum of phenotypes: one with dextro-transposition of the great arteries, one with congenital contractural arachnodactyly, one individual with a myofibrillar myopathy, and one fetal case with fetal akinesia with brain ischemia and neonatal death. Hence, the mode of inheritance should be changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thoracic aortic aneurysm or dissection (GMS) v5.7 | FBN2 | Ida Ertmanska Phenotypes for gene: FBN2 were changed from Congenital Contractural Arachnodactyly; Contractural arachnodactyly, congenital, 121050 to Contractural arachnodactyly, congenital, OMIM:121050; congenital contractural arachnodactyly, MONDO:0007363 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thoracic aortic aneurysm or dissection (GMS) v5.6 | FBN2 | Ida Ertmanska Publications for gene: FBN2 were set to 25944730; 29907982 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thoracic aortic aneurysm or dissection (GMS) v5.5 | FBN2 | Ida Ertmanska commented on gene: FBN2: Comment on mode of inheritance: There are 4 unrelated individuals reported in literature with biallelic FBN2 variants. However, these individuals presented with a spectrum of phenotypes: one with dextro-transposition of the great arteries, one with congenital contractural arachnodactyly, one individual with a myofibrillar myopathy, and one fetal case with fetal akinesia with brain ischemia and neonatal death. Hence, the mode of inheritance should remain MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Thoracic aortic aneurysm or dissection (GMS) v5.5 | FBN2 | Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | FBN2 | Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FBN2 | Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v7.33 | FBN2 | Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.16 | FBN2 | Ida Ertmanska commented on gene: FBN2: Comment on mode of inheritance: There are 4 unrelated individuals reported in literature with biallelic FBN2 variants. However, these individuals presented with a spectrum of phenotypes: one with dextro-transposition of the great arteries, one with congenital contractural arachnodactyly, one individual with a myofibrillar myopathy, and one fetal case with fetal akinesia with brain ischemia and neonatal death. Hence, the mode of inheritance should remain MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.16 | FBN2 | Ida Ertmanska Phenotypes for gene: FBN2 were changed from Contractural arachnodactyly, congenital, OMIM:121050 to Contractural arachnodactyly, congenital, OMIM:121050; congenital contractural arachnodactyly, MONDO:0007363 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.15 | FBN2 | Ida Ertmanska Publications for gene: FBN2 were set to 9737771; 10797416; 20799338 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ehlers Danlos syndrome with a likely monogenic cause v4.14 | FBN2 |
Ida Ertmanska changed review comment from: BIALLELIC CASES: PMID: 38791509 Zodanu et al., 2024 Proband B was prenatally diagnosed with dextro-transposition of the great arteries, based on a fetal echocardiogram at 20 weeks of gestation and required cardiac surgery at 0 and 5 days after birth. WES of proband B and his parents, showed compound heterozygous missense, c.518C>T and c.8230T>G (p.Tyr2744Asp), variants in the FBN2 in proband B; unaffected parents confirmed het for one variant each. PMID: 33571691 Kloth et al., 2021 Report of a 15-year-old girl with a severe form of congenital contractural arachnodactyly and novel biallelic variants in FBN2: the missense variant c.3563G > T/p.(Gly1188Val) from her unaffected father and the nonsense variant c.6831C > A/p.(Cys2277*) from her healthy mother. PMID: 28383543 Monies et al., 2017 Family 16DG0107 - male proband homozygous for FBN2 variant NM_001999.3:c.41T>G:p.(Leu14Arg) - het in unaffected parents and sibs. Variant not found in gnomAD v4. Proband presented at birth with clubfoot. At 13 yrs he had fatigue, mild to severe muscle weakness (severe in hip extensors), camptodactyly. The CK value was normal, but muscle biopsy showed myofibrillar disorganization. PMID: 25558065 Alazami et al., 2015 Large cohort of consanguineous families. Method: WES. Individual 12DG0104 had a FBN2 variant NM_001999:c.1064G>A, p.G355D, and presented with fetal akinesia with brain ischemia and neonatal death.; to: BIALLELIC CASES: PMID: 38791509 Zodanu et al., 2024 Proband B was prenatally diagnosed with dextro-transposition of the great arteries, based on a fetal echocardiogram at 20 weeks of gestation and required cardiac surgery at 0 and 5 days after birth. WES of proband B and his parents, showed compound heterozygous missense, c.518C>T and c.8230T>G (p.Tyr2744Asp), variants in the FBN2 in proband B; unaffected parents confirmed het for one variant each. PMID: 33571691 Kloth et al., 2021 Report of a 15-year-old girl with a severe form of congenital contractural arachnodactyly and novel biallelic variants in FBN2: the missense variant c.3563G > T/p.(Gly1188Val) from her unaffected father and the nonsense variant c.6831C > A/p.(Cys2277*) from her healthy mother. PMID: 28383543 Monies et al., 2017 Family 16DG0107 - male proband homozygous for FBN2 variant NM_001999.3:c.41T>G:p.(Leu14Arg) - het in unaffected parents and sibs. Variant not found in gnomAD v4. Proband presented at birth with clubfoot. At 13 yrs he had fatigue, mild to severe muscle weakness (severe in hip extensors), camptodactyly. The CK value was normal, but muscle biopsy showed myofibrillar disorganization. PMID: 25558065 Alazami et al., 2015 Large cohort of consanguineous families. Method: WES. Individual 12DG0104 had a FBN2 variant NM_001999:c.1064G>A, p.G355D, and presented with fetal akinesia with brain ischemia and neonatal death. FBN2 is associated with AD Contractural arachnodactyly, congenital, OMIM:121050 in OMIM. The association between FBN2 and AD congenital contractural arachnodactyly is classified as Definitive in ClinGen (Nov 2025, Hereditary Cardiovascular Disease GCEP). Resources accessed 6th Aug 2026. |
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| Ehlers Danlos syndrome with a likely monogenic cause v4.14 | FBN2 | Ida Ertmanska reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25558065, 28383543, 33571691, 38791509; Phenotypes: Contractural arachnodactyly, congenital, OMIM:121050, congenital contractural arachnodactyly, MONDO:0007363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 | LY96 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is only one family and functional evidence available in support of the disease association. The phenotype is variable across the two siblings from the same family. Hence, this gene can only be rated red with the current evidence.; to: Comment on list classification: There is only one family and functional evidence available in support of the disease association. The phenotype is variable across the two siblings from the same family. Hence, this gene can only be rated red with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 | LY96 | Achchuthan Shanmugasundram edited their review of gene: LY96: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 | LY96 | Achchuthan Shanmugasundram Classified gene: LY96 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 | LY96 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one family and functional evidence available in support of the disease association. The phenotype is variable across the two siblings from the same family. Hence, this gene can only be rated red with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.75 | LY96 | Achchuthan Shanmugasundram Gene: ly96 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.74 | LY96 | Achchuthan Shanmugasundram Phenotypes for gene: LY96 were changed from Inflammatory bowel disease; Pneumonia; Otitis media; Abnormal inflammatory response; Recurrent bacterial infections to inflammatory bowel disease, MONDO:0005265; pneumonia, MONDO:0005249; otitis media, MONDO:0005441 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 | LY96 | Achchuthan Shanmugasundram edited their review of gene: LY96: Changed phenotypes to: inflammatory bowel disease, MONDO:0005265, pneumonia, MONDO:0005249, otitis media, MONDO:0005441 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 | LY96 | Achchuthan Shanmugasundram reviewed gene: LY96: Rating: AMBER; Mode of pathogenicity: None; Publications: 36462957; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.17 | CAV3 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: CAV3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.17 | CAV3 | Ida Ertmanska commented on gene: CAV3: Comment on mode of inheritance: There are more than 3 unrelated individuals reported in literature with biallelic CAV3 variants and a caveolinopathy, which primarily manifests in exercise intolerance and elevated CK. Proximal weakness and hypertrophy of limbs are also often reported, though the disease is often mild and slow progressing. The severity of disease does not clearly correlate with the mode of inheritance. Based on available evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.8 | CAV3 | Ida Ertmanska commented on gene: CAV3: Comment on mode of inheritance: There are more than 3 unrelated individuals reported in literature with biallelic CAV3 variants and a caveolinopathy, which primarily manifests in exercise intolerance and elevated CK. Proximal weakness and hypertrophy of limbs are also often reported, though the disease is often mild and slow progressing. The severity of disease does not clearly correlate with the mode of inheritance. Based on available evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.8 | CAV3 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: CAV3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.17 | CAV3 | Ida Ertmanska Publications for gene: CAV3 were set to http://www.ncbi.nlm.nih.gov/books/NBK1408/ | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.16 | CAV3 | Ida Ertmanska Phenotypes for gene: CAV3 were changed from Rippling muscle disease 2, OMIM:606072; Myopathy, distal, Tateyama type, OMIM:614321 to caveolinopathy MONDO:0016146; Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease 2, OMIM:606072; rippling muscle disease 2, MONDO:0019947; distal myopathy, Tateyama type, MONDO:0013686 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.8 | CAV3 | Ida Ertmanska Publications for gene: CAV3 were set to 15668980; 12666119; 9536092; 11251997; 16730439 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.7 | CAV3 | Ida Ertmanska Phenotypes for gene: CAV3 were changed from Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease, OMIM:606072 to caveolinopathy MONDO:0016146; Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease 2, OMIM:606072; rippling muscle disease 2, MONDO:0019947; distal myopathy, Tateyama type, MONDO:0013686 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v2.18 | CAV3 | Ida Ertmanska Phenotypes for gene: CAV3 were changed from Rippling muscle disease, OMIM:606072; Myopathy, distal, Tateyama type, OMIM:614321 to caveolinopathy MONDO:0016146; Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease 2, OMIM:606072; rippling muscle disease 2, MONDO:0019947; distal myopathy, Tateyama type, MONDO:0013686 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v2.17 | CAV3 | Ida Ertmanska Publications for gene: CAV3 were set to 12666119; 15668980; 11251997; 27312022; 16730439; 9536092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v2.16 | CAV3 |
Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).; to: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 | PAX5 | Achchuthan Shanmugasundram Classified gene: PAX5 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 | PAX5 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only patient and functional evidence available in support of the disease association. Hence, this gene is rated amber on this panel with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.73 | PAX5 | Achchuthan Shanmugasundram Gene: pax5 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.6 | CAV3 |
Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign. --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGe; to: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign. --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGe |
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| Acute rhabdomyolysis v2.16 | CAV3 | Ida Ertmanska edited their review of gene: CAV3: Changed publications to: 9536092, 12666119, 15668980, 16730439, 18253147, 37166430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.72 | PAX5 | Achchuthan Shanmugasundram Phenotypes for gene: PAX5 were changed from hypogammaglobulinemia; reduced B cells; sensorimotor deficits; autism spectrum disorder to PAX5-related B lymphopenia and autism spectrum disorder, MONDO:0100299; Hypogammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 | CAV3 | Ida Ertmanska edited their review of gene: CAV3: Changed publications to: 9536092, 12666119, 15668980, 16730439, 18253147, 37166430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 | PAX5 | Achchuthan Shanmugasundram edited their review of gene: PAX5: Changed phenotypes to: PAX5-related B lymphopenia and autism spectrum disorder, MONDO:0100299, Hypogammaglobulinaemia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 | PAX5 | Achchuthan Shanmugasundram reviewed gene: PAX5: Rating: AMBER; Mode of pathogenicity: None; Publications: 35947077; Phenotypes: Hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 | CAV3 |
Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign. --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).; to: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign. --------------------- BIALLELIC CASES - review by Ivone Leong, copied from Rhabdomyolysis and metabolic muscle disorders panel PMID: 9536092, reported one patient with homozygous G56S. The patient was the only member of the family to be affected by disease (proximal muscle weakness in the first decade of life). The variant was not found in 200 controls. The patient's skeletal muscle biopsy looked normal and expression of dystrophin, sarcoglycans and caveolin-3 was normal. This variant was later reclassified as a VUS as PMID:11251997 identified 2 Brazilian patients with LGMD with heterozygous G55S. Both patients had onset in adulthood, calf hypertrophy, elevated creatine kinase, and difficulty walking. Muscle protein analyses from both patients were normal. Screening 200 normal controls showed 4 controls also had this variant. In OMIM: "Hamosh (2018) found that the G55S variant was present in heterozygous state in 3,142 of 277,064 alleles and in 184 homozygotes in the gnomAD database (January 24, 2018), calling into question the pathogenicity of the variant." PMID: 12666119, reported an Italian patient with severe rippling muscle disease (A92T) who was AR. Actually A93T. PMID: 15668980, the same authors of PMID: 12666119 reported 1 family with 2 affected sibs who have AR rippling muscle disease (same variant as above A92T). Unaffected parents were both heterozygous for the variant. The authors note that the parents were not known to be consanguineous but they are from the same small village in Germany. The authors also did a haplotype analysis and showed that this variant arose separately from the Italian case, suggesting that A92 might be a mutation hot spot. According to ClinVar, this variant has conflicting interpretations of pathogenicity (https://www.ncbi.nlm.nih.gov/clinvar/variation/8285/) PMID: 16730439, reports on 1 patient (AR) with mild proximal muscle weakness of the lower limbs. No other family members were available for further analysis. Patient is homozygous for a splice variant (IVS1+2T>C). --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026). |
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| Rhabdomyolysis and metabolic muscle disorders v6.6 | CAV3 | Ida Ertmanska edited their review of gene: CAV3: Changed publications to: 18253147, 37166430 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.6 | CAV3 |
Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).; to: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign. --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGe |
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| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 | CAV3 |
Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026).; to: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). PMID: 18253147 Traverso et al., 2008 Patient 1, a 58yo female, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, showed an autosomal recessive mutation CAV3 c.233C>T, p.(T78M). Neurological examination revealed generalized hypotonia, proximal weakness and hypotrophy of the upper limbs, and proximal hypotrophy and calf hypetrophy of the lower limbs. Variant has MAF = 0.008413 in gnomAD, including one homozygote - VUS leaning Benign. --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026). |
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| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 | CAV3 | Ida Ertmanska edited their review of gene: CAV3: Changed rating: GREEN; Changed publications to: 37166430; Changed phenotypes to: caveolinopathy MONDO:0016146, Myopathy, distal, Tateyama type, OMIM:614321, Rippling muscle disease 2, OMIM:606072, rippling muscle disease 2, MONDO:0019947, distal myopathy, Tateyama type, MONDO:0013686; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 | CAV3 | Ida Ertmanska commented on gene: CAV3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rhabdomyolysis and metabolic muscle disorders v6.6 | CAV3 |
Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).; to: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). --------------------- CAV3 is only associated with autosomal dominant disease entities in OMIM (Cardiomyopathy, familial hypertrophic, MIM:192600; Creatine phosphokinase, elevated serum, MIM:123320; Myopathy, distal, Tateyama type, MIM:614321; Rippling muscle disease 2, MIM:606072; Long QT syndrome 9, MIM:611818). The association between CAV3 and AD caveolinopathy (MONDO:0016146) was classified as Definitive in ClinGen (Muscular Dystrophies and Myopathies GCEP, Sept 2022). Resources accessed 6th Aug 2026). |
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| Rhabdomyolysis and metabolic muscle disorders v6.6 | CAV3 | Ida Ertmanska reviewed gene: CAV3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37166430; Phenotypes: caveolinopathy MONDO:0016146, Myopathy, distal, Tateyama type, OMIM:614321, Rippling muscle disease 2, OMIM:606072, rippling muscle disease 2, MONDO:0019947, distal myopathy, Tateyama type, MONDO:0013686; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v2.16 | CAV3 | Ida Ertmanska edited their review of gene: CAV3: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Acute rhabdomyolysis v2.16 | CAV3 |
Ida Ertmanska changed review comment from: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13).; to: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). |
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| Acute rhabdomyolysis v2.16 | CAV3 |
Ida Ertmanska commented on gene: CAV3: PMID: 37166430 Berling et al., 2023 Report of 23 patients from 16 unrelated families (from France, Portugal, Belgium, and Algeria) with CAV3 mutations. 52% of individuals had exercise intolerance, 80% showed calf hypertrophy, and muscle rippling was seen in 65%. No cardiac or respiratory involvement noted in this cohort. CK was elevated in all patients. 2 of 23 patients were homozygous for CAV3 mutations - table claims it's patients 6 & 7: P6 - French male, disease onset at 20yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). No muscle weakness, only symptom was exercise intolerance. P7 - Portugese male, NOT SYMPTOMATIC at 49 yrs; homozygous for CAV3: c.427_431del, p.Ile143Glyfs*55 (not in gnomAD v4). However, text says the CAV3: c.427_431del variant was homozygous in 2 sibs with rippling muscle and calf hypertrophy from Family F (P7 and P13). |
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| Acute rhabdomyolysis v2.16 | CAV3 | Ida Ertmanska reviewed gene: CAV3: Rating: GREEN; Mode of pathogenicity: None; Publications: 9536092, 12666119, 15668980, 16730439; Phenotypes: caveolinopathy MONDO:0016146, Myopathy, distal, Tateyama type, OMIM:614321, Rippling muscle disease 2, OMIM:606072, rippling muscle disease 2, MONDO:0019947, distal myopathy, Tateyama type, MONDO:0013686; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.15 | IKBKE | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases identified with monoallelic IKBKE variants and functional evidence is also available for these variants. However, different phenotypes were reported in these two patients (HSV-2 meningitis vs autoinflammatory disease). Hence, this gene can only be rated amber with the current evidence.; to: Comment on list classification: There are two unrelated cases identified with monoallelic IKBKE variants and functional evidence is also available for these variants. However, different phenotypes were reported in these two patients and only one of them have autoinflammatory disease (other with HSV-2 meningitis). Hence, this gene can only be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.15 | IKBKE | Achchuthan Shanmugasundram Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.15 | IKBKE |
Achchuthan Shanmugasundram gene: IKBKE was added gene: IKBKE was added to Autoinflammatory disorders. Sources: Expert Review Amber,Literature Mode of inheritance for gene: IKBKE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IKBKE were set to 37937644; 39524436 Phenotypes for gene: IKBKE were set to Herpes Simplex Virus type 2 (HSV-2) meningitis; autoinflammatory syndrome, MONDO:0019751 Penetrance for gene: IKBKE were set to unknown |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 | GINS4 | Achchuthan Shanmugasundram edited their review of gene: GINS4: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 | GINS4 | Achchuthan Shanmugasundram Classified gene: GINS4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 | GINS4 |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with biallelic GINS4 variants and with NK cell deficiency and neutropenia. This includes three unrelated patients with the same recurrent potentially founder variant (p.Val171Met) and two additional families reported with compound heterozygous variants (and one variant in both these families is p.Val171Leu). There is also extensive functional evidence available. Hence, this gene can be promoted to green rating in the next GMS update. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.71 | GINS4 | Achchuthan Shanmugasundram Gene: gins4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 | GINS4 | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 | GINS4 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: GINS4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 | GINS4 | Achchuthan Shanmugasundram Tag watchlist was removed from gene: GINS4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 | IKBKE | Achchuthan Shanmugasundram Classified gene: IKBKE as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 | IKBKE | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases identified with monoallelic IKBKE variants and functional evidence is also available for these variants. However, different phenotypes were reported in these two patients (HSV-2 meningitis vs autoinflammatory disease). Hence, this gene can only be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.70 | IKBKE | Achchuthan Shanmugasundram Gene: ikbke has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.69 | IKBKE | Achchuthan Shanmugasundram Phenotypes for gene: IKBKE were changed from Herpes Simplex Virus type 2 (HSV-2) meningitis; Mollaret meningitis to Herpes Simplex Virus type 2 (HSV-2) meningitis; autoinflammatory syndrome, MONDO:0019751 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.68 | IKBKE | Achchuthan Shanmugasundram Publications for gene: IKBKE were set to 37937644 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.67 | IKBKE | Achchuthan Shanmugasundram Mode of inheritance for gene: IKBKE was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 | IKBKE | Achchuthan Shanmugasundram edited their review of gene: IKBKE: Changed phenotypes to: Herpes Simplex Virus type 2 (HSV-2) meningitis, autoinflammatory syndrome, MONDO:0019751 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 | IKBKE | Achchuthan Shanmugasundram reviewed gene: IKBKE: Rating: AMBER; Mode of pathogenicity: None; Publications: 37937644, 39524436; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 | GINS4 | Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: GINS4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 | GINS4 | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: GINS4. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 | GINS4 | Achchuthan Shanmugasundram Classified gene: GINS4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 | GINS4 |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with the same recurrent potential founder variant (p.Val171Met) that is also found in homozygous state in one individual in gnomAD4.1.1. There are two additional families reported with compound heterozygous variants and one of these variants in both these cases are the same (p.Val171Leu). Hence, this gene is rated amber with the current evidence. However, 'watchlist' tag has been added to review the gene with any new evidence. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.66 | GINS4 | Achchuthan Shanmugasundram Gene: gins4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.65 | GINS4 | Achchuthan Shanmugasundram Phenotypes for gene: GINS4 were changed from NK cell deficiency; neutropenia; viral infections to combined immunodeficiency, MONDO:0015131 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.64 | GINS4 | Achchuthan Shanmugasundram Publications for gene: GINS4 were set to 36345943 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.63 | GINS4 | Achchuthan Shanmugasundram reviewed gene: GINS4: Rating: AMBER; Mode of pathogenicity: None; Publications: 36345943, 40510848, 40768335; Phenotypes: combined immunodeficiency, MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.94 | EIF1AX | Achchuthan Shanmugasundram Classified gene: EIF1AX as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.94 | EIF1AX | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Julia Baptista, there is sufficient evidence available (four unrelated cases) for the association of EIF1AX with intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.94 | EIF1AX | Achchuthan Shanmugasundram Gene: eif1ax has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.93 | EIF1AX |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: EIF1AX. Tag Q3_26_promote_green tag was added to gene: EIF1AX. |
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| Intellectual disability v10.93 | EIF1AX | Achchuthan Shanmugasundram Publications for gene: EIF1AX were set to PMID: 42337333 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.92 | EIF1AX | Achchuthan Shanmugasundram Phenotypes for gene: EIF1AX were changed from intellectual disability to neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.91 | EIF1AX | Achchuthan Shanmugasundram Mode of inheritance for gene: EIF1AX was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.90 | EIF1AX | Achchuthan Shanmugasundram reviewed gene: EIF1AX: Rating: GREEN; Mode of pathogenicity: None; Publications: 42337333; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.46 | PHB | Eleanor Williams commented on gene: PHB | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.90 | ZSCAN10 | Eleanor Williams Phenotypes for gene: ZSCAN10 were changed from Otofacial neurodevelopmental syndrome, OMIM:620910 to Otofacial neurodevelopmental syndrome, OMIM:620910; otofacial neurodevelopmental syndrome, MONDO:0975705 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.63 | NOX1 | Achchuthan Shanmugasundram Classified gene: NOX1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.63 | NOX1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are over 10 patients reported with inflammatory bowel disease (IBD) and with NOX1 variants, large cohort analyses suggest that NOX1 loss-of-function variants may not always present as a fully penetrant Mendelian disorder and that other genetic modifiers or environmental factors may contribute to disease pathogenesis. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.63 | NOX1 | Achchuthan Shanmugasundram Gene: nox1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.62 | NOX1 |
Achchuthan Shanmugasundram changed review comment from: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1. PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 05 August 2026).; to: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser in one patient; c.967G>A, p.Asp360Asn in two patients). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1. PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 inflammatory bowel disease (IBD) patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 05 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.62 | NOX1 |
Achchuthan Shanmugasundram changed review comment from: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1. PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen. ; to: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1. PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 05 August 2026). |
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| Cerebral vascular malformations v5.2 | PDCD10 | Alexandra Njegic reviewed gene: PDCD10: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 15543491, 31114296, 39173099; Phenotypes: Cerebral cavernous malformations-3; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital hypothyroidism v3.11 | DUOX2 | Arina Puzriakova Phenotypes for gene: DUOX2 were changed from Congenital hypothyroidism; Thryoid dyshormonogenesis 6, 607200; permanent congenital hypothyroidism; transient congenital hypothyroidism; eutopic gland-in-situ; goitre; borderline congenital hypothyroidism; iodide organification defect to Thyroid dyshormonogenesis 6, OMIM:607200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.62 | DUOX2 | Arina Puzriakova Phenotypes for gene: DUOX2 were changed from inflammatory bowel disease; MONDO:0005265; IBD; VEOIBD to inflammatory bowel disease, MONDO:0005265 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.25 | OSMR | Arina Puzriakova Phenotypes for gene: OSMR were changed from AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1, OMIM:105250; atopic eczema, MONDO:0004980 to Amyloidosis, primary localized cutaneous, 1, OMIM:105250; atopic eczema, MONDO:0004980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pigmentary skin disorders v5.12 | OSMR | Arina Puzriakova Phenotypes for gene: OSMR were changed from Amyloidosis cutis; PLCA1; AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1 to Amyloidosis, primary localized cutaneous, 1, OMIM:105250 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.46 | PHB | Ida Ertmanska Phenotypes for gene: PHB were changed from to optic atrophy, MONDO:0003608 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.45 | PHB | Ida Ertmanska Classified gene: PHB as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.45 | PHB | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Cassandra Smith, there is one pedigree reported in literature where a heterozygous missense variant in PHB1 segregated with optic atrophy. Hence, this gene can only be rated Red until more evidence emerges for the association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.45 | PHB | Ida Ertmanska Gene: phb has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.44 | PHB | Ida Ertmanska commented on gene: PHB | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.44 | PHB | Ida Ertmanska Tag new-gene-name tag was added to gene: PHB. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.89 | USP34 | Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: USP34. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.89 | USP34 | Ida Ertmanska edited their review of gene: USP34: Changed rating: GREEN; Changed phenotypes to: neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.89 | USP34 | Ida Ertmanska Phenotypes for gene: USP34 were changed from to neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.88 | USP34 | Ida Ertmanska Classified gene: USP34 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.88 | USP34 | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Benito Banos Pinero, there are 6 individuals reported in the literature with heterozygous USP34 variants (5 confirmed de novo) and a neurodevelopmental phenotype. Hence, this gene can be promoted to Green on Intellectual disability, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.88 | USP34 | Ida Ertmanska Gene: usp34 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.87 | USP34 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: USP34. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.87 | ZSCAN10 | Ida Ertmanska Classified gene: ZSCAN10 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.87 | ZSCAN10 | Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic ZSCAN10 variants and syndromic intellectual disability with motor developmental delay. Hence, this gene should be promoted to Green on Intellectual disability with MOI set to BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.87 | ZSCAN10 | Ida Ertmanska Gene: zscan10 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.86 | ZSCAN10 |
Ida Ertmanska gene: ZSCAN10 was added gene: ZSCAN10 was added to Intellectual disability. Sources: Literature Q3_26_promote_green tags were added to gene: ZSCAN10. Mode of inheritance for gene: ZSCAN10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZSCAN10 were set to 38386308; 40605417 Phenotypes for gene: ZSCAN10 were set to Otofacial neurodevelopmental syndrome, OMIM:620910 Review for gene: ZSCAN10 was set to GREEN Added comment: PMID: 38386308 Laugwitz et al., 2024 Report of 7 individuals from 5 unrelated families (3 consanguineous) with biallelic ZSCAN10 variants and a neurodevelopmental disorder with facial dysmorphism. All 7 probands harboured biallelic nonsense variants. Cognitive impairment was mild (1), moderate (3) or severe (3) in these patients, with moderate to profound delay of motor development. 4/7 probands also had a hearing impairment (1 with unilateral deafness only). Other less consistent features included microgenitalia (2/7), heart defects (1/7) and cleft palate (1/7). 3 individuals had unspecified vision impairment. PMID: 40605417 Alfalah et al., 2025 Research letter describing a male patient from a consanguineous Saudi family with mild cognitive impairment, moderate motor delay, ADHD, left SNHL, and vision impairment (myopia the vision is 20/40 bilateral ptosis). He had a clinical diagnosis of Goldenhar syndrome. He harboured a homozygous ZSCAN10 variant NM_032805.3: c.598_602del, p.Pro200Lysfs*48. Het parents unaffected. Sources: Literature |
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| Intellectual disability v10.85 | EIF1AX |
Julia Baptista gene: EIF1AX was added gene: EIF1AX was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: EIF1AX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: EIF1AX were set to PMID: 42337333 Phenotypes for gene: EIF1AX were set to intellectual disability Review for gene: EIF1AX was set to GREEN Added comment: PMID: 42337333- describes four de novo hemizygous EIF1AX variants (comprising three missense and one splice variant) in four male individuals exhibiting variable neurodevelopmental disorders, including developmental and language delays, autistic behavioral problems, and facial dysmorphisms. Functional studies using Drosophila models supported a LOF effect for (Lys64Glu) and p.(Asp90Gly) whilst no significant effect was seen for p.(Asn17Asp). Minigene analysis for the c.204 G > C showed aberrant mRNA splicing and a LOF allele. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.61 | NOX1 | Achchuthan Shanmugasundram Phenotypes for gene: NOX1 were changed from Inflammatory bowel disease; IBD; VEOIBD to inflammatory bowel disease, MONDO:0005265 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.60 | NOX1 | Achchuthan Shanmugasundram Publications for gene: NOX1 were set to 32064493; 26301257; 29091079 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.59 | NOX1 | Achchuthan Shanmugasundram Mode of inheritance for gene: NOX1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.58 | NOX1 |
Achchuthan Shanmugasundram changed review comment from: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1. PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in patients with pediatric-onset IBD.; to: PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1. PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.58 | HCK | Arina Puzriakova Publications for gene: HCK were set to 34536415 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.13 | XXYLT1 | Achchuthan Shanmugasundram Classified gene: XXYLT1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.13 | XXYLT1 | Achchuthan Shanmugasundram Gene: xxylt1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.12 | XXYLT1 | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: XXYLT1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.12 | XXYLT1 | Achchuthan Shanmugasundram Phenotypes for gene: XXYLT1 were changed from Retinal dystrophy to Cone-rod dystrophy, MONDO:0015993; Inherited retinal dystrophy, MONDO:0019118 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.11 | XXYLT1 | Achchuthan Shanmugasundram Publications for gene: XXYLT1 were set to PMID: 42530953 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.57 | KARS | Achchuthan Shanmugasundram Classified gene: KARS as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.57 | KARS | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer & Luke Stuart, this gene should be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.57 | KARS | Achchuthan Shanmugasundram Gene: kars has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.56 | KARS | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: KARS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.56 | KARS | Achchuthan Shanmugasundram Phenotypes for gene: KARS were changed from progressive leukoencephalopathy; peripheral neuropathy; deafness; antibody deficiency; hypogammaglobulinemia to Hypogammaglobulinemia; antibody deficiency | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.55 | KARS | Achchuthan Shanmugasundram Publications for gene: KARS were set to 37770806 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.10 | XXYLT1 | Luke Stuart reviewed gene: XXYLT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 42530953; Phenotypes: Cone-rod dystrophy (MONDO:0015993), Inherited retinal dystrophy (MONDO:0019118); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 | KARS | Luke Stuart reviewed gene: KARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 33942428, 37770806; Phenotypes: Hypogammaglobulinemia, antibody deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Retinal disorders v9.10 | XXYLT1 |
Siying Lin gene: XXYLT1 was added gene: XXYLT1 was added to Retinal disorders. Sources: Literature Mode of inheritance for gene: XXYLT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: XXYLT1 were set to PMID: 42530953 Phenotypes for gene: XXYLT1 were set to Retinal dystrophy Mode of pathogenicity for gene: XXYLT1 was set to Other Review for gene: XXYLT1 was set to GREEN Added comment: Biallelic XXYLT1 variants were identified in 7 affected individuals from 5 unrelated families (4 Finnish and 1 UK) with autosomal recessive inherited retinal disease. The recurrent splice variant was supported by RNA studies demonstrating aberrant splicing and loss of function, while the independent UK family harboured a distinct homozygous missense variant. These findings support XXYLT1 is a novel cause of autosomal recessive inherited retinal disease. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 | NOX1 | Achchuthan Shanmugasundram reviewed gene: NOX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26301257, 29091079, 32064493; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 | CD48 | Achchuthan Shanmugasundram Classified gene: CD48 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 | CD48 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients with two different variants affecting the same residue and functional evidence available in support of the association of CD48 gene with immune dysregulation. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.54 | CD48 | Achchuthan Shanmugasundram Gene: cd48 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.53 | CD48 | Achchuthan Shanmugasundram Phenotypes for gene: CD48 were changed from Hemophagocytic lymphohistiocytosis; Urticaria; Hives; Inflammation; Fever; Hepatosplenomegaly to inborn error of immunity, MONDO:0003778 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.52 | CD48 | Achchuthan Shanmugasundram Publications for gene: CD48 were set to 31419545 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.51 | CD48 | Achchuthan Shanmugasundram Mode of inheritance for gene: CD48 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 | CD48 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: CD48. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 | CD48 | Achchuthan Shanmugasundram reviewed gene: CD48: Rating: GREEN; Mode of pathogenicity: None; Publications: 31419545, 41984595; Phenotypes: inborn error of immunity, MONDO:0003778; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.14 | FGR | Achchuthan Shanmugasundram Entity copied from Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.14 | FGR |
Achchuthan Shanmugasundram gene: FGR was added gene: FGR was added to Autoinflammatory disorders. Sources: Expert Review Amber,Literature Q3_26_promote_green tags were added to gene: FGR. Mode of inheritance for gene: FGR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FGR were set to 31138708; 41920357 Phenotypes for gene: FGR were set to chronic recurrent multifocal osteomyelitis, MONDO:0009813; vasculitis, MONDO:0018882 Penetrance for gene: FGR were set to unknown Mode of pathogenicity for gene: FGR was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 | FGR |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants. 1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants, and functional evidence for these two variants and from mouse model available. 2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below) Based on these evidence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants. 1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants, and functional evidence for these two variants and from mouse model available. 2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below) Based on this evidence, this gene can be promoted to green rating in the next GMS update. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 | FGR |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants. 1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants and functional evidence for these two variants and from mouse model available. 2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below) Based on these evidence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants. 1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants, and functional evidence for these two variants and from mouse model available. 2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below) Based on these evidence, this gene can be promoted to green rating in the next GMS update. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 | FGR | Achchuthan Shanmugasundram Classified gene: FGR as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 | FGR |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two different autoinflammatory phenotypes reported with monoallelic FGR variants. 1. >10 unrelated cases with chronic recurrent multifocal osteomyelitis, of which two patients had missense variants and functional evidence for these two variants and from mouse model available. 2. One large family with vasculitis and functional evidence available for the variant (although reduced penetrance as reported in the review below) Based on these evidence, this gene can be promoted to green rating in the next GMS update. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.50 | FGR | Achchuthan Shanmugasundram Gene: fgr has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.49 | FGR |
Achchuthan Shanmugasundram changed review comment from: PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype. PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 31 July 2026).; to: PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype. PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease. Functional studies on p.Tyr523His variant showed ~50% reduced Fgr protein, enhanced STAT1/STAT5 signaling and increased CD11b/CD18 integrin expression. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 31 July 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.49 | FGR |
Achchuthan Shanmugasundram changed review comment from: PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype. PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:31138708 (2019) reported whole-exome sequencing of 99 Chronic recurrent multifocal osteomyelitis (CRMO) patients including 88 trios and 11 dyads, of which 11 different rare exonic heterozygous variants in FGR gene were identified in 13 probands. These include two missense variants, p.Arg118Trp found in SH3 domain and and p.Pro525Ser variant found in C-terminal tail. Functional analysis showed p.Arg118Trp variant decreased kinase activity, while p.Pro525Ser showed increased kinase activity (gain-of-function). Studies on Ali18 mice carrying a gain‑of‑function missense mutation in the C‑terminal regulatory region of Fgr shiwed that it reduces its negative regulatory phosphorylation, and this aberrant Fgr activity is necessary and sufficient to drive the spontaneous sterile osteomyelitis and systemic low bone mineral density inflammatory phenotype. PMID:41920357 (2026) reported three unrelated kindreds with sarcoma (Src) family of non-receptor tyrosine kinase (SFK)-associated vasculitis, of which one large family of 13 affected members across four generations was identified with a novel missense variant in FGR (p.Tyr523His). All clinically affected individuals (10) were heterozygous, while four unaffected members did not carry the variant. Two self-reported healthy members were also heterozygous, suggesting AD inheritance with incomplete penetrance or variable expressivity, although these two carriers have not undergone investigations for subclinical disease. This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 31 July 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.49 | FGR | Achchuthan Shanmugasundram Phenotypes for gene: FGR were changed from Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease to chronic recurrent multifocal osteomyelitis, MONDO:0009813; vasculitis, MONDO:0018882 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.48 | FGR | Achchuthan Shanmugasundram edited their review of gene: FGR: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.48 | FGR | Achchuthan Shanmugasundram Publications for gene: FGR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.47 | FGR | Achchuthan Shanmugasundram Mode of inheritance for gene: FGR was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 | FGR | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: FGR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 | FGR | Achchuthan Shanmugasundram reviewed gene: FGR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31138708, 41920357; Phenotypes: chronic recurrent multifocal osteomyelitis, MONDO:0009813, vasculitis, MONDO:0018882; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 | LY9 | Achchuthan Shanmugasundram Classified gene: LY9 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 | LY9 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (three unrelated cases and functional evidence) for the association of LY9 gene with this panel. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.46 | LY9 | Achchuthan Shanmugasundram Gene: ly9 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.45 | LY9 | Achchuthan Shanmugasundram edited their review of gene: LY9: Changed phenotypes to: inborn error of immunity, MONDO:0003778, Mycobacterium tuberculosis, susceptibility, MONDO:0000070 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.45 | LY9 | Achchuthan Shanmugasundram Phenotypes for gene: LY9 were changed from Tubercolosis to inborn error of immunity, MONDO:0003778; Mycobacterium tuberculosis, susceptibility, MONDO:0000070 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | LY9 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: LY9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | LY9 | Achchuthan Shanmugasundram reviewed gene: LY9: Rating: GREEN; Mode of pathogenicity: None; Publications: 40446017; Phenotypes: inborn error of immunity, MONDO:0003778; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | BIRC3 |
Achchuthan Shanmugasundram changed review comment from: PMID:42335979 (2026) reported the identification of rare and damaging BIRC3 variants in 14 patients from 10 unrelated families with Crohn's disease (CD) diagnosed between infancy and adulthood. They carried 8 distinct BIRC3 variants — 5 heterozygous missense/ nonsense variants (p.H312Y - recurrent in 2 families, p.T35A, p.P266R, p.C557X, p.D530H) causing pediatric- to adult-onset CD (age range <1 to 31 years), and 3 homozygous nonsense/ frameshift variants (p.Y522X, p.C588Y, p.X605Rext*10) in sibling pairs from consanguineous families, causing infantile-onset CD. Functional studies showed that BIRC3 (cIAP2) deficiency impairs RIPK1 ubiquitylation, causing RIPK1 autophosphorylation, resulting in increased epithelial cell death. Knock‑in cIAP2 (H312Y/+) mice and ciap1‑deficient zebrafish developed or exacerbated colitis, transcriptome analysis of mice organoids and zebrafish showed that BIRC3 deficiency led to inappropriate sustained activation of TNF‑responsive genes even without stimuli, and intestinal inflammation in BIRC3‑deficient models was attenuated by small‑molecule inhibition of RIPK1 or caspases. This gene has not yet been associated with relevant phenotypes in OMIM or ClinGen (last accessed 30 July 2026).; to: PMID:42335979 (2026) reported the identification of rare and damaging BIRC3 variants in 14 patients from 10 unrelated families with Crohn's disease (CD) diagnosed between infancy and adulthood. They carried 8 distinct BIRC3 variants — 5 heterozygous missense/ nonsense variants (p.H312Y - recurrent in 2 families and de novo in the index patient), p.T35A, p.P266R, p.C557X, p.D530H) causing pediatric- to adult-onset CD (age range <1 to 31 years), and 3 homozygous nonsense/ frameshift variants (p.Y522X, p.C588Y, p.X605Rext*10) in sibling pairs from consanguineous families, causing infantile-onset CD. Functional studies showed that BIRC3 (cIAP2) deficiency impairs RIPK1 ubiquitylation, causing RIPK1 autophosphorylation, resulting in increased epithelial cell death. Knock‑in cIAP2 (H312Y/+) mice and ciap1‑deficient zebrafish developed or exacerbated colitis, transcriptome analysis of mice organoids and zebrafish showed that BIRC3 deficiency led to inappropriate sustained activation of TNF‑responsive genes even without stimuli, and intestinal inflammation in BIRC3‑deficient models was attenuated by small‑molecule inhibition of RIPK1 or caspases. This gene has not yet been associated with relevant phenotypes in OMIM or ClinGen (last accessed 30 July 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | BIRC3 | Achchuthan Shanmugasundram Classified gene: BIRC3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | BIRC3 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (seven unrelated families with monoallelic variants and three unrelated families with biallelic variants) for the association of of BIRC3 with inflammatory bowel disease. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.44 | BIRC3 | Achchuthan Shanmugasundram Gene: birc3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.43 | BIRC3 | Achchuthan Shanmugasundram Phenotypes for gene: BIRC3 were changed from Inflammatory bowel disease; IBD; Crohn's disease to inborn error of immunity, MONDO:0003778; Crohn disease, MONDO:0005011 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.42 | BIRC3 | Achchuthan Shanmugasundram Publications for gene: BIRC3 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 | BIRC3 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: BIRC3. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 | BIRC3 | Achchuthan Shanmugasundram reviewed gene: BIRC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 42335979; Phenotypes: inborn error of immunity, MONDO:0003778, Crohn disease, MONDO:0005011; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 | MYB | Achchuthan Shanmugasundram Classified gene: MYB as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 | MYB | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients with heterozygous SNVs in Myb gene and functional evidence including mouse models available from peer-reviewed published scientific literature in support of the association of Myb with combined immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.41 | MYB | Achchuthan Shanmugasundram Gene: myb has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.40 | MYB | Achchuthan Shanmugasundram Phenotypes for gene: MYB were changed from Evans syndrome; Neutropenia; Autoimmune cytopenias; B cell lymphopenia to combined immunodeficiency, MONDO:0015131 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.39 | MYB | Achchuthan Shanmugasundram Mode of inheritance for gene: MYB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.38 | MYB | Achchuthan Shanmugasundram Publications for gene: MYB were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 | MYB | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: MYB. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 | MYB | Achchuthan Shanmugasundram reviewed gene: MYB: Rating: GREEN; Mode of pathogenicity: None; Publications: 20130238, 27577878, 29654210, 36168523; Phenotypes: combined immunodeficiency, MONDO:0015131; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Structural eye disease v5.7 | TBK1 | Luke Stuart reviewed gene: TBK1: Rating: RED; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 21447600, 33892047, 28984711; Phenotypes: low tension glaucoma (MONDO:0006837), juvenile open angle glaucoma (MONDO:0020367); Mode of inheritance: Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.55 | SP9 | Achchuthan Shanmugasundram Classified gene: SP9 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.55 | SP9 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available (three unrelated cases) for the association of SP9 to epilepsy, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.55 | SP9 | Achchuthan Shanmugasundram Gene: sp9 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.85 | SP9 | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.85 | SP9 | Achchuthan Shanmugasundram Classified gene: SP9 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.85 | SP9 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available (four unrelated cases) for the association of SP9 to developmental delay/ intellectual disability, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.85 | SP9 | Achchuthan Shanmugasundram Gene: sp9 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.85 | SP9 | Achchuthan Shanmugasundram Classified gene: SP9 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.85 | SP9 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available (four unrelated cases) for the association of SP9 to developmental delay/ intellectual disability, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.85 | SP9 | Achchuthan Shanmugasundram Gene: sp9 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.54 | SP9 |
Achchuthan Shanmugasundram gene: SP9 was added gene: SP9 was added to Early onset or syndromic epilepsy. Sources: Literature Q3_26_promote_green tags were added to gene: SP9. Mode of inheritance for gene: SP9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SP9 were set to 38288683 Phenotypes for gene: SP9 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: SP9 was set to GREEN Added comment: PMID:38288683 (2024) reported the identification of four different de novo heterozygous variants in SP9 as a cause of a novel form of interneuronopathy in five unrelated cases. Individual 1 is a male fetus with moderate ventriculomegaly and multiple periventricular and deep gray matter cystic/ischemic lesions (choroid plexus and periventricular cysts, bilateral GE and caudate signal abnormalities with restricted diffusion) identified on late third‑trimester MRI, leading to termination of pregnancy at 35 weeks’ gestation. This individual was identified with c.1133A>C (p.Glu378Ala) variant in SP9 gene. The age of other four individuals ranged from six months to six years and all had neurodevelopmental disorder of variable severity. A first clinical phenotype consisting of moderate intellectual disability (ID) associated with an ASD with or without epilepsy was present in individuals 2 and 5 who carried frameshift SP9 variants, p.c.1216del (p.His406ThrfsTer2) and c.1192_1207dup (p.Arg403Glnfs∗15), respectively. A second, more severe clinical phenotype consisting of epileptic encephalopathy was present in individuals 3 and 4, who both carried a missense variant c.1133A>G (p.Glu378Gly) involving the same glutamate residue in position 378 as individual 1. In summary, (global) developmental delay and/or intellectual disability was reported in four patients, while epilepsy was reported in three. This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet reported in OMIM (last accessed 30 July 2026). Sources: Literature |
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| Intellectual disability v10.84 | SP9 |
Achchuthan Shanmugasundram gene: SP9 was added gene: SP9 was added to Intellectual disability. Sources: Literature Q3_26_promote_green tags were added to gene: SP9. Mode of inheritance for gene: SP9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SP9 were set to 38288683 Phenotypes for gene: SP9 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: SP9 was set to GREEN Added comment: PMID:38288683 (2024) reported the identification of four different de novo heterozygous variants in SP9 as a cause of a novel form of interneuronopathy in five unrelated cases. Individual 1 is a male fetus with moderate ventriculomegaly and multiple periventricular and deep gray matter cystic/ischemic lesions (choroid plexus and periventricular cysts, bilateral GE and caudate signal abnormalities with restricted diffusion) identified on late third‑trimester MRI, leading to termination of pregnancy at 35 weeks’ gestation. This individual was identified with c.1133A>C (p.Glu378Ala) variant in SP9 gene. The age of other four individuals ranged from six months to six years and all had neurodevelopmental disorder of variable severity. A first clinical phenotype consisting of moderate intellectual disability (ID) associated with an ASD with or without epilepsy was present in individuals 2 and 5 who carried frameshift SP9 variants, p.c.1216del (p.His406ThrfsTer2) and c.1192_1207dup (p.Arg403Glnfs∗15), respectively. A second, more severe clinical phenotype consisting of epileptic encephalopathy was present in individuals 3 and 4, who both carried a missense variant c.1133A>G (p.Glu378Gly) involving the same glutamate residue in position 378 as individual 1. In summary, (global) developmental delay and/or intellectual disability was reported in four patients, while epilepsy was reported in three. This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet reported in OMIM (last accessed 30 July 2026). Sources: Literature |
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| Structural eye disease v5.7 | OPTN | Luke Stuart reviewed gene: OPTN: Rating: RED; Mode of pathogenicity: None; Publications: 34536459, 16043855, 33892047, 15326130, 38872230, 37530275; Phenotypes: Glaucoma 1, open angle, E, OMIM:137760, {Glaucoma, normal tension, susceptibility to}, OMIM:606657; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.12 | OGDH | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (five unrelated families) for the association of biallelic OGDH variants with global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (four unrelated families) for the association of biallelic OGDH variants with childhood-onset dystonia. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.12 | OGDH | Achchuthan Shanmugasundram Entity copied from Intellectual disability v10.83 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.12 | OGDH |
Achchuthan Shanmugasundram gene: OGDH was added gene: OGDH was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Expert Review Amber,Literature Q3_26_promote_green tags were added to gene: OGDH. Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OGDH were set to 32383294; 36520152 Phenotypes for gene: OGDH were set to Oxoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759 |
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| Intellectual disability v10.83 | OGDH | Achchuthan Shanmugasundram Classified gene: OGDH as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.83 | OGDH | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (five unrelated families) for the association of biallelic OGDH variants with global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.83 | OGDH | Achchuthan Shanmugasundram Gene: ogdh has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.82 | OGDH | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: OGDH. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.82 | OGDH |
Achchuthan Shanmugasundram gene: OGDH was added gene: OGDH was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OGDH were set to 32383294; 36520152 Phenotypes for gene: OGDH were set to Oxoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759 Review for gene: OGDH was set to GREEN Added comment: PMID:32383294 (2021) reported two siblings identified with a homozygous missense variant c.959A>G (p.Asn320Ser) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. PMID:36520152 (2023) reported four unrelated individuals with 3 different homozygous OGDH variants and presenting with a neurodevelopmental disorder characterised by global developmental delay, movement disorder, and metabolic abnormalities. There are six patients from five families reported in total with four different homozygous variants in OGDH gene and with a neurodevelopmental disorder with metabolic and movement abnormalities. Age of onset of the disease ranged from 6 weeks of age to 3 years old. All described individuals shared the clinical features of global developmental delay, hypotonia, metabolic acidosis and increased serum lactate. Additional shared clinical features included dystonia (5/6), microcephaly (3/4), abnormal nasal bridge morphology (3/6), hyperammonemia (3/6), hyperglutaminemia (3/3 who were tested), and elevated alpha-ketoglutarate in the urine (2/4 who were tested). This gene has been associated with relevant phenotype in OMIM (MIM #203740, last accessed 29 July 2026) and in Gene2Phenotype (with 'moderate' rating on the DD panel). This gene has also been associated with mitochondrial disease (MONDO:0044970) with 'Definitive' rating by the Mitochondrial Diseases GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009318). Sources: Literature |
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| Mitochondrial disorders v10.18 | OGDH | Achchuthan Shanmugasundram Classified gene: OGDH as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.18 | OGDH |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with biallelic OGDH variants and functional evidence available in support of the association. OGDH is part of a multicomplex enzyme involved in the Kreb cycle and this gene is associated with mitochondrial disease with 'Definitive' rating by Mitochondrial Diseases GCEP in ClinGen. However, expert review has been requested from NHSE as the recommendation for promotion to green rating has previously been disagreed by the NHSE suggesting that this gene is not associated with primary mitochondrial disease. |
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| Mitochondrial disorders v10.18 | OGDH | Achchuthan Shanmugasundram Gene: ogdh has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.17 | OGDH |
Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: OGDH. Tag Q3_26_promote_green tag was added to gene: OGDH. |
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| Mitochondrial disorders v10.17 | OGDH | Achchuthan Shanmugasundram Phenotypes for gene: OGDH were changed from Alpha-ketoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759 to Oxoglutarate dehydrogenase deficiency, OMIM:203740; oxoglutaricaciduria, MONDO:0008759 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.16 | OGDH | Achchuthan Shanmugasundram reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 32383294, 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, OMIM:203740, oxoglutaricaciduria, MONDO:0008759; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.81 | NPTN | Achchuthan Shanmugasundram Classified gene: NPTN as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.81 | NPTN | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (8 unrelated patients) for the association of monoallelic NPTN variants with mild-severe intellectual disability/ developmental delay. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.81 | NPTN | Achchuthan Shanmugasundram Gene: nptn has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.80 | NPTN | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: NPTN. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.80 | NPTN |
Achchuthan Shanmugasundram gene: NPTN was added gene: NPTN was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NPTN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NPTN were set to 42387534 Phenotypes for gene: NPTN were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 Review for gene: NPTN was set to GREEN Added comment: PMID:42387534 (2026) reported a cohort of eight individuals with seven different heterozygous variants in NPTN, seven of which are of de novo origin. The patients presented with an overlapping, but unspecific phenotype, All eight individuals presented with developmental delay (DD) and/or intellectual disability (ID) ranging from mild to severe (severe in four, moderate in two and mild in two). Seven individuals were diagnosed with autism spectrum disorder and six were reported with subtle dysmorphic facial features. Four individuals had variants (three variants) affecting the two hNp isoforms, hNp55 and hNp65 and other four variants affect only the neuron-specific hNp65 isoform. It was observed that the severity of ID/DD and other clinical findings correlate with the impact on both hNp isoforms (severe) or only on the hNp65 isoform (mild/moderate). Functional evidence from human cell line, cultured primary rodent neurons, and in vivo in Drosophila melanogaster showed that the missense variants are inefficiently expressed and inefficiently support PMCA levels, resulting in failed cytosolic Ca(2+) regulation. Haploinsuffient Nptn+/− mice expressed reduced amounts of both Np and PMCA. In a social behavior test, Nptn+/− mice displayed loss of preference for a novel mouse representing an endophenotype analog to social deficits that characterize autism. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 29 July 2026). Sources: Literature |
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| Retinal disorders v9.10 | PRDM13 | Eleanor Williams commented on gene: PRDM13 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.79 | GTPBP1 |
Achchuthan Shanmugasundram Tag Q3_25_promote_green was removed from gene: GTPBP1. Tag Q3_26_promote_green tag was added to gene: GTPBP1. |
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| Differences in sex development v4.22 | TBX6 |
Luke Stuart gene: TBX6 was added gene: TBX6 was added to Differences in sex development. Sources: Literature Mode of inheritance for gene: TBX6 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TBX6 were set to 36049007; 23954021 Phenotypes for gene: TBX6 were set to Mullerian aplasia (MONDO:0019128); Mayer-Rokitansky-Kuster-Hauser syndrome (MONDO:0017771) Review for gene: TBX6 was set to AMBER Added comment: Ma et al. 2022 (PMID 36049007): 622 Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) probands, 16 rare heterozygous TBX6 variants, all single alleles with no biallelic or in-trans genotypes. Several variants were supported by in vitro functional evidence (splice/frameshift c.423G>A p.Leu141Leu, c.839+5G>A; reduced protein c.422T>C p.Leu141Pro, c.745G>A Val249Met; reduced transactivation c.10C>T, c.400G>A; mislocalisation c.356G>A p.Arg119His plus one prior canonical splice variant c.621+1G>A. Against diagnostic-grade rating: segregation studies showed multiple non manifesting female carriers suggesting incomplete penetrance (unaffected carrier mother, c.10C>T p.Pro4Ser; two of three carrier sisters with normal uterus, c.356G>A p.Arg119His), penetrance of the Müllerian phenotype is low among TBX6 LoF and 16p11.2-deletion carriers generally, and no second in-trans allele was found. The authors propose an digenic/oligogenic model in which TBX6 confers risk of urogenital phenotypes. No family showed penetrant monogenic segregation. Sandbacka et al. 2013 (PMID 23954021): ascertained series of 112 mullerain aplasia (MA) patients vs 200 controls. Heterozygous whole-gene TBX6/16p11.2 deletion in 5/112, three of whom also had skeletal/vertebral findings; this recurrent deletion is found in unaffected and non-reproductive-phenotype carriers elsewhere, indicating low penetrance of this phenotype. Splice variant c.622-2A>T in two patients was predicted LoF but RT-PCR was inconclusive. Two recurrent missense variants (p.Gly162Ser, p.Arg272Gln) were enriched in affecteds but also frequent in controls. No segregation data was shown. Two patients were homozygous for both recurrent TBX6 missense variants (p.Gly162Ser, p.Arg272Gln): one also carried a heterozygous missense variant in LHX1 (p.Pro312His), another a candidate gene for MRKHS, the other an 11q13.4 deletion. A third patient, heterozygous for both TBX6 recurrent missense variants, also carried LHX1 p.Pro312His. Overall: both studies support risk association and complex/oligogenic inheritance, but neither provides segregation, completed functional validation of a penetrant effect, or convincing evidence free of confounding co-occurring variants. The evidence does not meet criteria for penetrant monogenic disease reportable in a diagnostic setting; amber rating is appropriate. This phenotype regarding TBX6 is not cited in OMIM. Sources: Literature |
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| Dystonia, chorea or related movement disorder, childhood onset v8.11 | GTPBP1 | Achchuthan Shanmugasundram Classified gene: GTPBP1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.11 | GTPBP1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated families reported with biallelic GTPBP1 variants and with movement disorder. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.11 | GTPBP1 | Achchuthan Shanmugasundram Gene: gtpbp1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.10 | GTPBP1 |
Achchuthan Shanmugasundram gene: GTPBP1 was added gene: GTPBP1 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTPBP1 were set to 38118446 Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MONDO:0975745 Review for gene: GTPBP1 was set to AMBER Added comment: PMID:38118446 (2024) reported a cohort of 20 individuals from 16 families with distinct neurodevelopmental disorders (NDDs) and syndromic facial features and identified with biallelic variants in either GTPBP1 or GTPBP2 genes. Of these, four patients from three unrelated families were identified with homozygous variants in GTPBP1 gene. Two families have different NMD-predicted nonsense variants and the third has a missense variant, and all are absent from gnomad v4.1.1. The shared clinical features of the syndrome include microcephaly, severe/ profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. In addition, abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Abnormal hand movements and tremor of hands and jaws were reported in 2 patients from 2 families with GTPBP1 variants. This gene has been associated with relevant phenotypes in OMIM (MIM #620888, last accessed 29 July 2026) and in Gene2Phenotype ('moderate' rating on the DD panel). Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v9.20 | GTPBP1 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated families reported with biallelic GTPBP1 variants and with cerebellar atrophy. Hence, this gene should be rated amber with the current evidence.; to: Comment on list classification: There are two unrelated families reported with biallelic GTPBP1 variants and with cerebellar atrophy. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.20 | GTPBP1 | Achchuthan Shanmugasundram Classified gene: GTPBP1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.20 | GTPBP1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated families reported with biallelic GTPBP1 variants and with cerebellar atrophy. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.20 | GTPBP1 | Achchuthan Shanmugasundram Gene: gtpbp1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.19 | GTPBP1 |
Achchuthan Shanmugasundram gene: GTPBP1 was added gene: GTPBP1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTPBP1 were set to 38118446 Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MONDO:0975745 Review for gene: GTPBP1 was set to AMBER Added comment: PMID:38118446 (2024) reported a cohort of 20 individuals from 16 families with distinct neurodevelopmental disorders (NDDs) and syndromic facial features and identified with biallelic variants in either GTPBP1 or GTPBP2 genes. Of these, four patients from three unrelated families were identified with homozygous variants in GTPBP1 gene. Two families have different NMD-predicted nonsense variants and the third has a missense variant, and all are absent from gnomad v4.1.1. The shared clinical features of the syndrome include microcephaly, severe/ profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. In addition, abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cerebellar atrophy was reported in 3 patients from 2 families with GTPBP1 variants. This gene has been associated with relevant phenotypes in OMIM (MIM #620888, last accessed 29 July 2026) and in Gene2Phenotype ('moderate' rating on the DD panel). Sources: Literature |
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| Early onset or syndromic epilepsy v9.53 | GTPBP1 | Achchuthan Shanmugasundram Classified gene: GTPBP1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.53 | GTPBP1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated patients reported with biallelic GTPBP1 variants and with epilepsy. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.53 | GTPBP1 | Achchuthan Shanmugasundram Gene: gtpbp1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.52 | GTPBP1 |
Achchuthan Shanmugasundram gene: GTPBP1 was added gene: GTPBP1 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTPBP1 were set to 38118446 Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MONDO:0975745 Review for gene: GTPBP1 was set to AMBER Added comment: PMID:38118446 (2024) reported a cohort of 20 individuals from 16 families with distinct neurodevelopmental disorders (NDDs) and syndromic facial features and identified with biallelic variants in either GTPBP1 or GTPBP2 genes. Of these, four patients from three unrelated families were identified with homozygous variants in GTPBP1 gene. Two families have different NMD-predicted nonsense variants and the third has a missense variant, and all are absent from gnomad v4.1.1. The shared clinical features of the syndrome include microcephaly, severe/ profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. In addition, abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Epilepsy was reported in 2 patients from 2 families with GTPBP1 variants. This gene has been associated with relevant phenotypes in OMIM (MIM #620888, last accessed 29 July 2026) and in Gene2Phenotype ('moderate' rating on the DD panel). Sources: Literature |
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| Intellectual disability v10.79 | GTPBP1 | Achchuthan Shanmugasundram Classified gene: GTPBP1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.79 | GTPBP1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated patients reported with biallelic GTPBP1 variants and with neurodevelopmental impairment. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.79 | GTPBP1 | Achchuthan Shanmugasundram Gene: gtpbp1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.78 | GTPBP1 | Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: GTPBP1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.78 | GTPBP1 |
Achchuthan Shanmugasundram gene: GTPBP1 was added gene: GTPBP1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GTPBP1 were set to 38118446 Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, OMIM:620888; neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MONDO:0975745 Review for gene: GTPBP1 was set to GREEN Added comment: PMID:38118446 (2024) reported a cohort of 20 individuals from 16 families with distinct neurodevelopmental disorders (NDDs) and syndromic facial features and identified with biallelic variants in either GTPBP1 or GTPBP2 genes. Of these, four patients from three unrelated families were identified with homozygous variants in GTPBP1 gene. Two families have different NMD-predicted nonsense variants and the third has a missense variant, and all are absent from gnomad v4.1.1. The shared clinical features of the syndrome include microcephaly, severe/ profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. In addition, abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Severe/ profound neurodevelopmental impairment was present in 3 patients from 3 families with GTPBP1 variants. This gene has been associated with relevant phenotypes in OMIM (MIM #620888, last accessed 29 July 2026) and in Gene2Phenotype ('moderate' rating on the DD panel). Sources: Literature |
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| Intestinal failure or congenital diarrhoea v3.17 | DUOX2 | Ida Ertmanska edited their review of gene: DUOX2: Changed phenotypes to: inflammatory bowel disease, MONDO:0005265 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intestinal failure or congenital diarrhoea v3.17 | DUOX2 | Ida Ertmanska Phenotypes for gene: DUOX2 were changed from inflammatory bowel disease; MONDO:0005265 to inflammatory bowel disease, MONDO:0005265 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 | DUOX2 | Ida Ertmanska Tag watchlist_moi tag was added to gene: DUOX2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 | DUOX2 |
Ida Ertmanska commented on gene: DUOX2: MONOALLELIC CASES: PMID: 26301257 Hayes et al., 2015 2 male probands, diagnosed with IBD / ulcerative colitis at 4.7 and 4.3 yrs. Het for DUOX2 missense variants. Adding watchlist_moi tag to monitor for heterozygous case reports. |
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| Intestinal failure or congenital diarrhoea v3.16 | DUOX2 | Ida Ertmanska Tag Q3_26_promote_green was removed from gene: DUOX2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intestinal failure or congenital diarrhoea v3.16 | DUOX2 | Ida Ertmanska Classified gene: DUOX2 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intestinal failure or congenital diarrhoea v3.16 | DUOX2 | Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic DUOX2 variants and very early onset IBD, including bloody diarrhea. However, these cases do not meet the Test Directory criterion of neonatal onset (first 28 days of life). Hence, the gene should remain Red on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intestinal failure or congenital diarrhoea v3.16 | DUOX2 | Ida Ertmanska Gene: duox2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intestinal failure or congenital diarrhoea v3.15 | DUOX2 |
Ida Ertmanska edited their review of gene: DUOX2: Added comment: PMID: 26301257 - 2 male probands, diagnosed with IBD / ulcerative colitis at 4.7 and 4.3 yrs. Het for DUOX2 missense variants. PMID: 28683258 - Male proband comp het for NM_014080.4:c.1825G>A; p.P609S and NM_014080.4:c.857G>A; R286H in DUOX2. He developed pancolitis with bloody diarrhea at the age of 3. PMID: 35429653 - report of a 1-year-old boy diagnosed with VEO-IBD after presenting with bloody diarrhea. He had pancolitis and an extensive small intestinal ulcerative lesion at age 4 years. PMID: 38075699 - Female proband diagnosed with IBD at 1 month. The infant was asymptomatic with no intestinal symptoms such as abdominal pain, rectal bleeding, perianal disease, diarrhea, or intestinal obstruction. The only sign of intestinal involvement was increased inflammatory markers.; Changed rating: RED |
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| Intestinal failure or congenital diarrhoea v3.15 | DUOX2 | Ida Ertmanska Classified gene: DUOX2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intestinal failure or congenital diarrhoea v3.15 | DUOX2 | Ida Ertmanska Gene: duox2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intestinal failure or congenital diarrhoea v3.14 | DUOX2 |
Ida Ertmanska gene: DUOX2 was added gene: DUOX2 was added to Intestinal failure or congenital diarrhoea. Sources: Literature Q3_26_promote_green tags were added to gene: DUOX2. Mode of inheritance for gene: DUOX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DUOX2 were set to 26301257; 28683258; 35429653; 38075699 Phenotypes for gene: DUOX2 were set to inflammatory bowel disease; MONDO:0005265 Review for gene: DUOX2 was set to GREEN Added comment: Literature review by Boaz Palterer (University of Florence), copied from Primary immunodeficiency or monogenic inflammatory bowel disease: DUOX2 encodes Dual Oxidase 2, an H2O2-producing NADPH oxidase primarily expressed at the apical membranes of enterocytes, where it plays a critical role in maintaining intestinal microbial homeostasis and innate immune defense. While biallelic variants in DUOX2 are classically associated with congenital hypothyroidism (Thyroid dyshormonogenesis 6; OMIM 607200), a distinct phenotype linking DUOX2 deficiency to Inborn Errors of Immunity (IEI) and very early-onset inflammatory bowel disease (VEO-IBD) has been reported in several case reports. The initial association was reported when inactivating missense variants in DUOX2 were identified in VEO-IBD patients, resulting in significantly reduced reactive oxygen species (ROS) production by intestinal epithelial cells and defective host resistance to enteric pathogens like Campylobacter jejuni (Hayes et al., 2015). More recently, the phenotypic spectrum has been expanded to include monogenic neonatal-onset IBD. Patients with compound heterozygous DUOX2 variants have presented with severe intestinal inflammation and colon stenosis shortly after birth, displaying significantly decreased catalytic activity without concurrent clinical hypothyroidism (Finocchi et al, Kyodo et al. Crawford et al. ). Hayes described 2 patient with heterozgous DUOX2 VUS and VEOIBD https://pmc.ncbi.nlm.nih.gov/articles/PMC4539615/ Finocchi et al described 1 month old with VEOIBD with compound heterozygous VUS in DUOX2 https://pubmed.ncbi.nlm.nih.gov/38075699/ Kyodo et al. described 1 year old with VEOIBD with compound heterozygous VUS in DUOX2 https://pubmed.ncbi.nlm.nih.gov/35429653/ Crawford et al, additional case report: 5-year-old male with compound heterozygous VUS in DUOX2 https://rupress.org/jhi/article/1/CIS2025/CIS2025abstract.49/277486/Biallelic-DUOX2-Variants-and-the-Link-to-Very Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.37 | DUOX2 | Ida Ertmanska Phenotypes for gene: DUOX2 were changed from Inflammatory bowel disease; IBD; VEOIBD to inflammatory bowel disease; MONDO:0005265; IBD; VEOIBD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.36 | DUOX2 | Ida Ertmanska Publications for gene: DUOX2 were set to 38075699; 26301257; 35429653 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.35 | DUOX2 | Ida Ertmanska Mode of inheritance for gene: DUOX2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.34 | DUOX2 | Ida Ertmanska Classified gene: DUOX2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.34 | DUOX2 | Ida Ertmanska Gene: duox2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.33 | DUOX2 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: DUOX2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.33 | DUOX2 | Ida Ertmanska reviewed gene: DUOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26301257, 28683258, 35429653, 38075699; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.24 | OSMR |
Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 8 unrelated individuals reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, this gene can be promoted to Green at the next GMS update.; to: Comment on mode of inheritance: There are 8 unrelated individuals reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, the mode of inheritance should be updated from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted (associated with dominant Amyloidosis) to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. |
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| Rare genetic inflammatory skin disorders v4.24 | OSMR | Ida Ertmanska commented on gene: OSMR: Comment on mode of inheritance: There are 8 unrelated individuals reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, this gene can be promoted to Green at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.24 | OSMR | Ida Ertmanska Phenotypes for gene: OSMR were changed from AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1, OMIM:105250 to AMYLOIDOSIS, PRIMARY LOCALIZED CUTANEOUS, 1, OMIM:105250; atopic eczema, MONDO:0004980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.23 | OSMR | Ida Ertmanska Publications for gene: OSMR were set to 18179886 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.22 | OSMR | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: OSMR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.22 | OSMR | Ida Ertmanska reviewed gene: OSMR: Rating: GREEN; Mode of pathogenicity: None; Publications: 41783139, 42221229; Phenotypes: atopic eczema, MONDO:0004980; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.33 | OSMR | Ida Ertmanska edited their review of gene: OSMR: Changed phenotypes to: atopic eczema, MONDO:0004980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.33 | OSMR | Ida Ertmanska Phenotypes for gene: OSMR were changed from Atopic dermatitis; eosinophilia; elevated IgE to Atopic dermatitis; eosinophilia; elevated IgE; atopic eczema, MONDO:0004980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.32 | OSMR | Ida Ertmanska Publications for gene: OSMR were set to 42221229 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.31 | OSMR | Ida Ertmanska Classified gene: OSMR as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.31 | OSMR | Ida Ertmanska Added comment: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, this gene can be promoted to Green at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.31 | OSMR | Ida Ertmanska Gene: osmr has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.30 | OSMR | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: OSMR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.30 | OSMR |
Ida Ertmanska changed review comment from: PMID: 41783139 Andersen et al., 2026 Study described a patient (57-year-old man of Caucasian Danish descent) presenting with elevated IgE levels, atopic eczema, chronic pulmonary aspergillosis, frequent secondary staphylococcal skin infections and pustules, and bone fractures. Blood profiling showed elevated IgE-expressing plasmablasts and peripheral T follicular helper cells and atypical memory B cells. WGS showed that P1 was homozygous for a missense variant c.1307T>A, p.Val436Asp. A significant reduction in OSMR surface expression on patient dermal fibroblasts compared to controls was found by flow cytometry. A skin biopsy showed perivascular inflammation with lymphocytes and eosinophils but no amyloid deposits. PMID: 42221229 Samra et al., 2026 Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected. In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4.; to: PMID: 41783139 Andersen et al., 2026 Study described a patient (57-year-old man of Caucasian Danish descent) presenting with elevated IgE levels, atopic eczema, chronic pulmonary aspergillosis, frequent secondary staphylococcal skin infections and pustules, and bone fractures. Blood profiling showed elevated IgE-expressing plasmablasts and peripheral T follicular helper cells and atypical memory B cells. WGS showed that P1 was homozygous for a missense variant c.1307T>A, p.Val436Asp. A significant reduction in OSMR surface expression on patient dermal fibroblasts compared to controls was found by flow cytometry. A skin biopsy showed perivascular inflammation with lymphocytes and eosinophils but no amyloid deposits. PMID: 42221229 Samra et al., 2026 Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected. In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4. OSMR is associated with AD Amyloidosis, primary localized cutaneous, 1, OMIM:105250; no recessive association added in OMIM, G2P, or ClinGen (accessed 29th July 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.30 | OSM |
Ida Ertmanska gene: OSM was added gene: OSM was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: OSM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OSM were set to 39847438 Phenotypes for gene: OSM were set to bone marrow disorder, MONDO:0003225 Review for gene: OSM was set to RED Added comment: PMID: 39847438 Garrigue et al., 2025 Report of 3 female sibs from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterized by profound anemia, thrombocytopenia, and neutropenia. Patients showed no susceptibility to infection, nor any bone or psychomotor defects. WES detected a homozygous OSM: c.507_508insG; Arg170AlafsTer124 variant in P1 and P2, confirmed het in unaffected parents. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 | OSMR | Ida Ertmanska edited their review of gene: OSMR: Changed publications to: 41783139, 42221229 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 | OSMR |
Ida Ertmanska changed review comment from: PMID: 42221229 Samra et al., 2026 Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected. In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4.; to: PMID: 41783139 Andersen et al., 2026 Study described a patient (57-year-old man of Caucasian Danish descent) presenting with elevated IgE levels, atopic eczema, chronic pulmonary aspergillosis, frequent secondary staphylococcal skin infections and pustules, and bone fractures. Blood profiling showed elevated IgE-expressing plasmablasts and peripheral T follicular helper cells and atypical memory B cells. WGS showed that P1 was homozygous for a missense variant c.1307T>A, p.Val436Asp. A significant reduction in OSMR surface expression on patient dermal fibroblasts compared to controls was found by flow cytometry. A skin biopsy showed perivascular inflammation with lymphocytes and eosinophils but no amyloid deposits. PMID: 42221229 Samra et al., 2026 Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected. In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 | OSMR |
Ida Ertmanska changed review comment from: PMID: 42221229 Samra et al., 2026 Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected.; to: PMID: 42221229 Samra et al., 2026 Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected. In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 | OSMR | Ida Ertmanska reviewed gene: OSMR: Rating: GREEN; Mode of pathogenicity: None; Publications: 42221229; Phenotypes: Amyloidosis, primary localized cutaneous, 1, OMIM:105250, atopic eczema, MONDO:0004980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 | SEPT6 | Ida Ertmanska Tag watchlist tag was added to gene: SEPT6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.29 | SEPT6 | Ida Ertmanska Phenotypes for gene: SEPT6 were changed from Congenital neutropenia; B cell deficiency; T cell lymphopenia; Abnormal newborn screening for SCID; Hypersegmented neutrophils; Myelodysplasia; Decreased circulating B cells; Leukopenia to severe congenital neutropenia, MONDO:0018542; Immunodeficiency, HP:0002721; Congenital neutropenia; B cell deficiency; T cell lymphopenia; Abnormal newborn screening for SCID; Hypersegmented neutrophils; Myelodysplasia; Decreased circulating B cells; Leukopenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.28 | SEPT6 | Ida Ertmanska Classified gene: SEPT6 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.28 | SEPT6 | Ida Ertmanska Added comment: Comment on list classification: To date, there are 2 unrelated male individuals reported in literature with hemizygous variants in SEPT6 and severe congenital neutropenia. Hence, this gene should remain Amber with the current evidence. A 'watchlist' tag was added in anticipation of more case reports. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.28 | SEPT6 | Ida Ertmanska Gene: sept6 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 | SEPT6 |
Ida Ertmanska edited their review of gene: SEPT6: Added comment: PMID: 42088107 Gunderman et al., 2026 2 male sibs with severe nonsyndromic congenital neutropenia, absent circulating B cells, marrow mature myeloid, and rare plasma cell accumulation, as well as tetraploidy, with disease reversal following myeloablative HSCT. Older sibling had T-cell receptor excision circles (TRECs) of 9 copies (normal >20), while younger brother had 0 copies. No infectious symptoms were present. WGS detected a hemizygous SEPTIN6 (NM_145799.4) c.1282T>A; p.*428Kext*9 variant in both brothers (het in the unaffected mother) - diagnosed with X-linked SEPTIN6-related immunodeficiency. PMID: 34677878 Renella et al., 2023 Report of a Caucasian male proband, presented with severe neutropenia associated with dysmyelopoiesis and tetraploidy as a newborn. The absolute neutrophil count (ANC) was 0.5 G/L at birth, subsequently 0-0.2 G/L. At age 1 year he underwent an allogeneic HLA-DQ-mismatched unrelated HSCT. WGS detected a hemizygous c.1282T>C, p.*428Glnext*9 variant in SEPT6. Second somatic SEPT6 variant was detected in cis: c.43C>T, p.Arg15* (14% of reads). This gene is not yet associated with a disease entity in OMIM, ClinGen, or G2P (accessed 29th July 2026).; Changed rating: AMBER; Changed publications to: 42088107, 34677878; Changed phenotypes to: severe congenital neutropenia, MONDO:0018542, Immunodeficiency, HP:0002721; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females |
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| Early onset or syndromic epilepsy v9.51 | ATP2B2 |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: ATP2B2. Tag Q3_26_promote_green tag was added to gene: ATP2B2. |
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| Dystonia, chorea or related movement disorder, childhood onset v8.9 | ATP2B2 | Achchuthan Shanmugasundram Classified gene: ATP2B2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.9 | ATP2B2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients reported with other movement disorders including dystonia (in one patient). As this is a small subset of total patients reported with neurological/ neurodevelopmental phenotypes (14 patients from 13 unrelated families), this gene should be rated amber with current evidence. However, 'watchlist' tag has been added to review the gene in light of any new evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.9 | ATP2B2 | Achchuthan Shanmugasundram Gene: atp2b2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.8 | ATP2B2 |
Achchuthan Shanmugasundram gene: ATP2B2 was added gene: ATP2B2 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature watchlist tags were added to gene: ATP2B2. Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP2B2 were set to 29655659; 37675773; 39367743 Phenotypes for gene: ATP2B2 were set to neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807 Mode of pathogenicity for gene: ATP2B2 was set to Other Review for gene: ATP2B2 was set to AMBER Added comment: PMID:29655659 (2018) reported a novel missense variant (p.Val1143Phe) in PMCA2/ ATP2B2 gene in a 27-year old male patient presenting with congenital cerebellar ataxia but with no overt signs of deafness. This patient presented with delayed motor development requesting clinical attention at age 5 months, had dysmetria and intentional tremor at age 3 and showed obvious gait ataxia at age 4. The patient was also reported with impaired speech and moderate intellectual disability. Brain MRI studies revealed global cerebellar atrophy without cortical and brainstem involvement. PMID:37675773 (2023) reported seven individuals with rare, predicted deleterious heterozygous ATP2B2 variants, including 5 missense substitutions and 2 frameshift variants. De novo status was confirmed for six of these variants. All individuals displayed a spectrum of neurological abnormalities ranging from ataxia (5/7 patients) and other movement disorders including dystonic features (3 patients) to complex neurodevelopmental manifestations with intellectual disability, global developmental delay, and seizures (6 patients). Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects. PMID:39367743 (2025) reported six previously unreported patients from five unrelated families with four different missense variants and one frameshift variant (p.Leu1089GlnfsTer60). All missense variants were confirmed de novo, while the frameshift variant is paternally inherited in one and of unknown inheritance in other. These patients shared phenotypic features with the previously described patients including developmental delay and intellectual disability (all six patients), cognitive disturbances, autistic features epilepsy (3 patients), ataxia (3 patients) and other movement disorders (one patient). Striking cerebellar atrophy was observed in one affected individual. In total, there are 13 patients (from 12 families) with (global) developmental delay/ intellectual disability, 9 patients (from eight families) with seizures, 9 patients (from nine families) with ataxia and 4 patients (from four families) reported with other movement disorders including dystonia. This gene has been associated with hearing loss in both OMIM (MIM #619804, last accessed 29 July 2026) and ClinGen ('Definitive' rating for autosomal dominant nonsyndromic hearing loss (MONDO:0019587) by Hearing Loss GCEP), but not with the neurological/ neurodevelopmental phenotypes in these resources. Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v9.18 | ATP2B2 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with ataxia (nine families), this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with childhood-onset ataxia (nine families), this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.18 | ATP2B2 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with intellectual disability (nine families), this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with ataxia (nine families), this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.51 | ATP2B2 | Achchuthan Shanmugasundram Classified gene: ATP2B2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.51 | ATP2B2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with seizures (eight families), this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.51 | ATP2B2 | Achchuthan Shanmugasundram Gene: atp2b2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.50 | ATP2B2 | Achchuthan Shanmugasundram Phenotypes for gene: ATP2B2 were changed from Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities to neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 | SEPT6 | Ida Ertmanska commented on gene: SEPT6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 | SEPT6 | Ida Ertmanska Tag new-gene-name tag was added to gene: SEPT6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.49 | ATP2B2 | Achchuthan Shanmugasundram Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.48 | ATP2B2 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: ATP2B2 was changed from None to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.77 | USP34 |
Benito Banos Pinero gene: USP34 was added gene: USP34 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: USP34 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: USP34 were set to 42315110; 39050773; 28573701 Review for gene: USP34 was set to GREEN Added comment: PMID: 42315110 described 6 patients with truncating variants, five of them confirmed de novo with a phenotype of global developmental delay, craniofacial dysmorphism, marked speech impairment, variable autism spectrum disorder, and distal limb anomalies. USP34 is intolerant to Lof variants (pLI=1). No phenotypes associated with this gene in OMIM. USP34 is part of the 2p15p16.1 region, copy number losses in this region cause a neurodevelopmental disorder characterised by developmental delay/intellectual disability, ASD, microcephaly, short stature, dysmorphic features and multiple congenital anomalies (HI score 3 in clingen). The authors suggest that the phenotype associated with isolated loss of USP34 overlaps substantially with that reported in 2p15p16.1 microdeletion syndrome, while suggesting that some features seen in larger deletions may reflect the contribution of additional genes within the interval. PMID: 39050773 reports a 9 year old boy wit mild intellectual disability and dysmorphic features with a de novo 50kb 2p15 copy number loss including only USP34 and XPO1. PMID: 28573701reports two additional cases with deletions of only USP34 and XPO1 in a prenatal case with brain anomalies and dysmorphic features. The second case with dysmorphic features, behavioural issues, rhizomelic shortening of the limbs and agenesis of the corpus callosum, deletion was de novo. Sources: Literature |
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| Early onset or syndromic epilepsy v9.47 | ATP2B2 | Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.46 | ATP2B2 | Achchuthan Shanmugasundram reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29655659, 37675773, 39367743; Phenotypes: neurodevelopmental disorder, MONDO:0700092, cerebellar ataxia, MONDO:0000437, epilepsy, MONDO:0005027, intellectual disability,MONDO:0001071, inherited dystonia, MONDO:0044807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 | HCK | Ida Ertmanska Phenotypes for gene: HCK were changed from Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296 autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.26 | HCK | Ida Ertmanska Mode of inheritance for gene: HCK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.18 | ATP2B2 | Achchuthan Shanmugasundram Classified gene: ATP2B2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.18 | ATP2B2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with intellectual disability (nine families), this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.18 | ATP2B2 | Achchuthan Shanmugasundram Gene: atp2b2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.22 | HCK | Ida Ertmanska Classified gene: HCK as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.22 | HCK | Ida Ertmanska Added comment: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Cutaneous vasculitis was the most consistent feature, present in all 5 probands. Hence, this gene can be promoted to Green at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.22 | HCK | Ida Ertmanska Gene: hck has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.17 | ATP2B2 | Achchuthan Shanmugasundram Phenotypes for gene: ATP2B2 were changed from Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities to neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.16 | ATP2B2 | Achchuthan Shanmugasundram Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.15 | ATP2B2 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: ATP2B2 was changed from None to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.14 | ATP2B2 | Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.13 | ATP2B2 |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: ATP2B2. Tag Q3_26_promote_green tag was added to gene: ATP2B2. |
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| Intellectual disability v10.77 | ATP2B2 | Achchuthan Shanmugasundram Classified gene: ATP2B2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.77 | ATP2B2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with intellectual disability (12 families), this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.77 | ATP2B2 | Achchuthan Shanmugasundram Gene: atp2b2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare genetic inflammatory skin disorders v4.21 | HCK |
Ida Ertmanska gene: HCK was added gene: HCK was added to Rare genetic inflammatory skin disorders. Sources: Literature Q3_26_promote_green tags were added to gene: HCK. Mode of inheritance for gene: HCK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HCK were set to 34536415; 41382121; 41920357; doi.org/10.11648/j.ajp.20190504.15 Phenotypes for gene: HCK were set to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296; autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204 Review for gene: HCK was set to GREEN Added comment: PMID: 41920357 Price-Kuehne et al., 2026 Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage. Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy. PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025 Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK. PMID: 34536415 Kanderova et al. 2022 Described a single patient with an autoinflammatory phenotype characterized by early-onset cutaneous vasculitis and lung inflammation leading to fibrosis. A de novo truncating mutation (p.Tyr515*) in the HCK leading to the loss of the C-terminal inhibitory tyrosine Tyr522 was identified. Variant pathogenicity was confirmed ex vivo in primary cells and in vitro in transduced cell lines. doi: 10.11648/j.ajp.20190504.15 Bronz et al., 2019 Family with suspected Finkelstein-Seidlmayer disease (benign small-vessel leukocytoclastic vasculitis) - affected mother and her 3 sons. History of red-to-purpuric skin lesions with neonatal onset, no systemic involvement. WES detected a heterozygous HCK variant c.1555G>T; p.Glu519* in all 4 affected individuals. Variant not present in gnomAD v4.1.1. Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v9.13 | ATP2B2 | Achchuthan Shanmugasundram reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29655659, 37675773, 39367743; Phenotypes: neurodevelopmental disorder, MONDO:0700092, cerebellar ataxia, MONDO:0000437, epilepsy, MONDO:0005027, intellectual disability,MONDO:0001071, inherited dystonia, MONDO:0044807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 | HCK | Ida Ertmanska changed review comment from: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals. Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.; to: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals (PMIDs: 34536415, 41382121) . Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.76 | ATP2B2 | Achchuthan Shanmugasundram Phenotypes for gene: ATP2B2 were changed from Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities to neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 | HCK | Ida Ertmanska changed review comment from: Comment on list classification: There are now 4 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals. Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease.; to: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals. Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.75 | ATP2B2 | Achchuthan Shanmugasundram Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.74 | ATP2B2 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: ATP2B2 was changed from None to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.16 | HCK | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: HCK. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.13 | HCK | Ida Ertmanska Publications for gene: HCK were set to 34536415; 41382121; 41920357 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.73 | ATP2B2 | Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.12 | HCK | Ida Ertmanska edited their review of gene: HCK: Changed publications to: 34536415, 41382121, 41920357, doi.org/10.11648/j.ajp.20190504.15 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.12 | HCK | Ida Ertmanska changed review comment from: Comment on list classification: There are now 4 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Hence, this gene can be promoted to Green at the next GMS update.; to: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Hence, this gene can be promoted to Green at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.72 | ATP2B2 | Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.71 | ATP2B2 |
Achchuthan Shanmugasundram Tag Q3_26_expert_review was removed from gene: ATP2B2. Tag Q3_26_promote_green tag was added to gene: ATP2B2. |
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| Intellectual disability v10.71 | ATP2B2 |
Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: ATP2B2. Tag Q3_26_NHS_review tag was added to gene: ATP2B2. |
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| Pulmonary Fibrosis, Familial v1.16 | HCK | Ida Ertmanska Phenotypes for gene: HCK were changed from Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296; autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.15 | HCK | Ida Ertmanska Publications for gene: HCK were set to 34536415; 41382121; 41920357; https://doi.org/10.11648/j.ajp.20190504.15 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.71 | ATP2B2 | Achchuthan Shanmugasundram reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 29655659, 37675773, 39367743; Phenotypes: neurodevelopmental disorder, MONDO:0700092, cerebellar ataxia, MONDO:0000437, epilepsy, MONDO:0005027, intellectual disability,MONDO:0001071, inherited dystonia, MONDO:0044807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.14 | HCK | Ida Ertmanska Publications for gene: HCK were set to 34536415 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.13 | HCK | Ida Ertmanska Mode of inheritance for gene: HCK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.12 | HCK | Ida Ertmanska Classified gene: HCK as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.12 | HCK | Ida Ertmanska Added comment: Comment on list classification: There are now 5 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Pulmonary fibrosis findings were noted in 3 unrelated cases. Hence, this gene can be promoted to Green at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.12 | HCK | Ida Ertmanska Gene: hck has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pulmonary Fibrosis, Familial v1.11 | HCK | Ida Ertmanska reviewed gene: HCK: Rating: GREEN; Mode of pathogenicity: None; Publications: 41382121, 41920357; Phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296, autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.12 | HCK | Ida Ertmanska Classified gene: HCK as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.12 | HCK | Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Hence, this gene can be promoted to Green at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.12 | HCK | Ida Ertmanska Gene: hck has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 | HCK | Ida Ertmanska Classified gene: HCK as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 | HCK | Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated families reported in literature with heterozygous HCK variants and autoinflammatory features, most commonly cutaneous and/or pulmonary vasculitis. Recurrent infections were noted in 2 unrelated individuals. Hence, the Autoinflammatory disorders panel may be more appropriate for this gene - leaving as Amber on Primary immunodeficiency or monogenic inflammatory bowel disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.25 | HCK | Ida Ertmanska Gene: hck has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Autoinflammatory disorders v3.11 | HCK |
Ida Ertmanska gene: HCK was added gene: HCK was added to Autoinflammatory disorders. Sources: Literature Q3_26_promote_green tags were added to gene: HCK. Mode of inheritance for gene: HCK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HCK were set to 34536415; 41382121; 41920357 Phenotypes for gene: HCK were set to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296; autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204 Review for gene: HCK was set to GREEN Added comment: PMID: 41920357 Price-Kuehne et al., 2026 Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage. Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy. PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025 Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK. PMID: 34536415 Kanderova et al. 2022 Described a single patient with an autoinflammatory phenotype characterized by early-onset cutaneous vasculitis and lung inflammation leading to fibrosis. A de novo truncating mutation (p.Tyr515*) in the HCK leading to the loss of the C-terminal inhibitory tyrosine Tyr522 was identified. Variant pathogenicity was confirmed ex vivo in primary cells and in vitro in transduced cell lines. doi: 10.11648/j.ajp.20190504.15 Bronz et al., 2019 Family with suspected Finkelstein-Seidlmayer disease (benign small-vessel leukocytoclastic vasculitis) - affected mother and her 3 sons. History of red-to-purpuric skin lesions with neonatal onset, no systemic involvement. WES detected a heterozygous HCK variant c.1555G>T; p.Glu519* in all 4 affected individuals. Variant not present in gnomAD v4.1.1. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.24 | HCK |
Ida Ertmanska changed review comment from: PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025 Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK. PMID: 41920357 Price-Kuehne et al., 2026 Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage. Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy.; to: PMID: 41920357 Price-Kuehne et al., 2026 Family A - female proband with systemic vasculitis due to a de novo heterozygous variant in HCK c.1545 C > A, p.(Tyr515Ter) - exome seq; she was treated with allogeneic haematopoietic stem cell transplantation. She subsequently developed epistaxis, haemolacria and blood-stained stools leading to iron-deficiency anaemia requiring transfusion. From 18 months of age, she developed chronic cough and haemoptysis; chest CT scan demonstrated enlarged hilar lymph nodes and bilateral inflammatory changes and pulmonary haemorrhage. Family B - male proband with a cutaneous-limited phenotype (purpuric rash, predominantly affecting the limbs, starting at 4hrs after birth); Skin biopsy showed leukocytoclastic vasculitis; WES identified a novel HCK missense variant c.1565A > T, (p.Tyr522Phe). Proband's father is het for the same HCK variant, and also had neonatal-onset leukocytoclastic vasculitis, now healthy. PMID: 41382121 Berdeli, Ismayilova, & Gürbüz 2025 Report of a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and suspected recurrent lower respiratory tract infections since age 1.5 years. No cutaneous manifestations were observed, but elevated acute-phase reactants and pulmonary findings were noted. WES revealed a heterozygous splice variant c.1016-5T>C in HCK. doi: 10.11648/j.ajp.20190504.15 Bronz et al., 2019 Family with suspected Finkelstein-Seidlmayer disease (benign small-vessel leukocytoclastic vasculitis) - affected mother and her 3 sons. History of red-to-purpuric skin lesions with neonatal onset, no systemic involvement. WES detected a heterozygous HCK variant c.1555G>T; p.Glu519* in all 4 affected individuals. Variant not present in gnomAD v4.1.1. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.24 | HCK | Ida Ertmanska reviewed gene: HCK: Rating: AMBER; Mode of pathogenicity: None; Publications: 41382121, 41920357; Phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296, autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.3 | OGDH | Achchuthan Shanmugasundram Classified gene: OGDH as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.3 | OGDH |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also some functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects. Hence, this gene can be rated amber with 'watchlist' tag added to review gene rating in light of any new evidence. |
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| Hereditary ataxia, adult onset v9.3 | OGDH | Achchuthan Shanmugasundram Gene: ogdh has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.2 | OGDH | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: OGDH. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.2 | OGDH | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.2 | OGDH | Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.44 | OGDH | Achchuthan Shanmugasundram Entity copied from Hereditary neuropathy or pain disorder v8.30 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Optic neuropathy v6.44 | OGDH |
Achchuthan Shanmugasundram gene: OGDH was added gene: OGDH was added to Optic neuropathy. Sources: Expert Review Red,Expert list Mode of inheritance for gene: OGDH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: OGDH were set to 42266417 Phenotypes for gene: OGDH were set to peripheral neuropathy, MONDO:0005244; cerebellar ataxia, MONDO:0000437; hereditary optic atrophy, MONDO:0043878 Mode of pathogenicity for gene: OGDH was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments |
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| Hereditary ataxia, adult onset v9.2 | OGDH | Achchuthan Shanmugasundram Entity copied from Hereditary neuropathy or pain disorder v8.30 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary ataxia, adult onset v9.2 | OGDH |
Achchuthan Shanmugasundram gene: OGDH was added gene: OGDH was added to Hereditary ataxia with onset in adulthood. Sources: Expert Review Red,Expert list Mode of inheritance for gene: OGDH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: OGDH were set to 42266417 Phenotypes for gene: OGDH were set to peripheral neuropathy, MONDO:0005244; cerebellar ataxia, MONDO:0000437; hereditary optic atrophy, MONDO:0043878 Mode of pathogenicity for gene: OGDH was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments |
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| Hereditary neuropathy or pain disorder v8.30 | OGDH | Achchuthan Shanmugasundram Classified gene: OGDH as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.30 | OGDH | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one patient and functional evidence from Drosophila models available in support of the disease association. This gene should be rated red with current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.30 | OGDH | Achchuthan Shanmugasundram Gene: ogdh has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.29 | OGDH | Achchuthan Shanmugasundram Phenotypes for gene: OGDH were changed from peripheral neuropathy; cerebellar ataxia; optic neuropathy to peripheral neuropathy, MONDO:0005244; cerebellar ataxia, MONDO:0000437; hereditary optic atrophy, MONDO:0043878 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.28 | OGDH | Achchuthan Shanmugasundram edited their review of gene: OGDH: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.28 | OGDH | Achchuthan Shanmugasundram reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 42266417; Phenotypes: peripheral neuropathy, MONDO:0005244, cerebellar ataxia, MONDO:0000437, hereditary optic atrophy, MONDO:0043878; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.6 | APOPT1 | Achchuthan Shanmugasundram Classified gene: APOPT1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.6 | APOPT1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic APOPT1 variants with childhood-onset spasticity (at least five unrelated cases). Hence, this gene can be promoted to green rating on this panel in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.6 | APOPT1 | Achchuthan Shanmugasundram Gene: apopt1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.5 | APOPT1 | Achchuthan Shanmugasundram commented on gene: APOPT1: The 'new-gene-name' tag has been added as the official HGNC gene symbol for APOPT1 is COA8. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.5 | APOPT1 | Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: APOPT1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.5 | APOPT1 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: APOPT1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary spastic paraplegia, childhood onset v9.5 | APOPT1 |
Achchuthan Shanmugasundram gene: APOPT1 was added gene: APOPT1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature Mode of inheritance for gene: APOPT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: APOPT1 were set to 25175347 Phenotypes for gene: APOPT1 were set to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; mitochondrial complex IV deficiency, nuclear type 17, MONDO:0033652; hereditary spastic paraplegia, MONDO:0019064 Review for gene: APOPT1 was set to GREEN Added comment: PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. Across the six individuals with APOPT1 mutations, all show infantile or childhood‑onset mitochondrial disease with profound COX deficiency, a characteristic cavitating leukodystrophy on MRI predominantly affecting posterior cerebral white matter and corpus callosum, and evidence of peripheral neuropathy. Clinically, they range from acute neurometabolic decompensation with spastic tetraparesis, seizures and cognitive impairment to much milder phenotypes with preserved cognition, but all have a chronic, long‑surviving course with stabilization or partial recovery of motor function despite persistent structural white matter changes. All patients except one of the two siblings presented with spastic tetraparesis with onset in early childhood (2-5 years of age). This gene has been associated with relevant phenotype in OMIM (MIM #619061, last accessed 28 July 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and in ClinGen (associated with 'definitive' rating for mitochondrial disease (MONDO:0044970) by Mitochondrial Diseases GCEP - https://search.clinicalgenome.org/CCID:004493). Sources: Literature |
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| Hereditary neuropathy or pain disorder v8.28 | APOPT1 | Achchuthan Shanmugasundram Classified gene: APOPT1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.28 | APOPT1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients with biallelic APOPT1 variants and presenting with neuropathy. Hence, this gene can be promoted to green rating on this panel in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.28 | APOPT1 | Achchuthan Shanmugasundram Gene: apopt1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.27 | APOPT1 | Achchuthan Shanmugasundram commented on gene: APOPT1: The 'new-gene-name' tag has been added as the official HGNC gene symbol for APOPT1 is COA8. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.27 | APOPT1 | Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: APOPT1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.27 | APOPT1 | Achchuthan Shanmugasundram Phenotypes for gene: APOPT1 were changed from 25175347; 38098475Encephalopathic episodes; loss of developmental milestones; seizures; spasticity; cavitating leukodystrophy to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; mitochondrial complex IV deficiency, nuclear type 17, MONDO:0033652; peripheral neuropathy, MONDO:0005244 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.26 | APOPT1 |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: APOPT1. Tag Q3_26_promote_green tag was added to gene: APOPT1. |
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| Hereditary neuropathy or pain disorder v8.26 | APOPT1 |
Achchuthan Shanmugasundram changed review comment from: PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. The clinical features of all six patients varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. Peripheral neuropathy was reported in two patients; to: PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. Across the six individuals with APOPT1 mutations, all show infantile or childhood‑onset mitochondrial disease with profound COX deficiency, a characteristic cavitating leukodystrophy on MRI predominantly affecting posterior cerebral white matter and corpus callosum, and evidence of peripheral neuropathy. Clinically, they range from acute neurometabolic decompensation with spastic tetraparesis, seizures and cognitive impairment to much milder phenotypes with preserved cognition, but all have a chronic, long‑surviving course with stabilization or partial recovery of motor function despite persistent structural white matter changes. Sensorimotor polyneuropathy was reported in three of the six patients. PMID:38098475 (2023) reported two female siblings from an Italian family with mitochondrial myopathy. Patient 1 presented with generalised epilepsy and retinitis pigmentosa at 10 years of age. She had cramps and myalgia after exercise and bilateral hearing loss since early adulthood. Last neurological examination (52 years of age) showed bilateral ptosis, muscle weakness, peripheral neuropathy, mild dysarthria, dysphonia and cognitive impairment. Muscle biopsy had shown the presence of ragged-red fibers. Patient 2 presented with fatigability, myalgia, and hearing loss. Neurological examination showed ptosis and muscle weakness. Muscle biopsy displayed a diffuse reduction of COX activity staining and ragged-red fibers. Both sisters presented secondary amenorrhea. A novel homozygous variant in COA8 (APOPT1) was identified via whole-exome sequencing in the probands (c.170_173dupGACC, p.Pro59fs). This gene has been associated with relevant phenotype in OMIM (MIM #619061, last accessed 28 July 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and in ClinGen (associated with 'definitive' rating for mitochondrial disease (MONDO:0044970) by Mitochondrial Diseases GCEP - https://search.clinicalgenome.org/CCID:004493). |
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| Intellectual disability v10.71 | GPN2 |
Luke Stuart gene: GPN2 was added gene: GPN2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GPN2 were set to 42392036 Phenotypes for gene: GPN2 were set to Intellectual disability (MONDO:0001071) Review for gene: GPN2 was set to RED Added comment: Smith et al. 2026 (PMID 42392036) investigated a Perrault syndrome cohort via exome sequencing. All individuals had congenital or perinatal bilateral sensorineural hearing loss (SNHL) and primary ovarian insufficiency (POI; females). Neurological findings were reported in 2/3 families (F2 and F3) in which affected individuals harbored the same homozygous missense GPN2 variant, c.664A>G p.(Asn222Asp). Family F3: a single proband presented with mild intellectual disability, in addition to profound SNHL and primary amenorrhea; cerebellar atrophy was noted on brain MRI. Family F2: two affected sisters presented with bilateral profound SNHL, POI, and cerebellar ataxia; brain MRI also showed cerebellar atrophy. No intellectual disability was noted. No additional putative variants were identified in any genes linked to Perrault syndrome, SNHL, or POI. N.B. Haplotype analysis in the affected members of families F2 and F3 revealed a shared homozygous region of 662 kb encompassing the GPN2 locus, indicative of a shared ancestor. Consequently, the neurological findings derive from a single recurrent variant on a potentially shared genetic background. Suggested rating: Red (low evidence); a single proband with mild intellectual disability is reported; no animal model or other functional evidence currently supports pathogenicity or validates a disease mechanism linking GPN2 to intellectual disability. Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v9.13 | GPN2 |
Luke Stuart gene: GPN2 was added gene: GPN2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GPN2 were set to 42392036 Phenotypes for gene: GPN2 were set to Cerebellar ataxia (MONDO:0000437) Review for gene: GPN2 was set to RED Added comment: Smith et al. 2026 (PMID 42392036) investigated a Perrault syndrome cohort via exome sequencing. Family F2 comprised two affected sisters with bilateral profound sensorineural hearing loss (SNHL), primary ovarian insufficiency (POI), and cerebellar ataxia. Brain MRI revealed cerebellar atrophy in both. Both were homozygous for GPN2 c.664A>G p.Asn222Asp. Family F3 comprised a single affected proband presenting with profound SNHL, primary amenorrhea, and mild intellectual disability, also homozygous for GPN2 c.664A>G p.Asn222Asp. Cerebellar atrophy was noted on brain MRI. N.B. Haplotype analysis in the affected members of families F2 and F3 revealed a shared homozygous region of 662 kb encompassing the GPN2 locus, indicative of a shared ancestor. Age at onset for affected probands is unknown, however age at last examination was in the 2nd or 3rd decade (supplemental data), suggesting early onset. Before this study, no Mendelian disease had been attributed to GPN2 or its paralogs, GPN1 and GPN3; no animal model exists supporting pathogenicity or delineating the potential mechanism. Conclusion: A single variant with potential founder effect is implicated in ataxia (n= 2 probands from 1 family)/ cerebellar atrophy (n=3 probands from 2 families); age of onset for the probands cited is unknown. Suggest red rating (low evidence). Sources: Literature |
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| Fetal anomalies v7.33 | DHCR7 | Arina Puzriakova Publications for gene: DHCR7 were set to 31840946 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.108 | DHCR7 | Arina Puzriakova Classified gene: DHCR7 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.108 | DHCR7 | Arina Puzriakova Gene: dhcr7 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.107 | TAZ | Arina Puzriakova Classified gene: TAZ as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.107 | TAZ | Arina Puzriakova Gene: taz has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.106 | RYR1 | Arina Puzriakova Classified gene: RYR1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.106 | RYR1 | Arina Puzriakova Gene: ryr1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.105 | PTH1R | Arina Puzriakova Classified gene: PTH1R as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.105 | PTH1R | Arina Puzriakova Gene: pth1r has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.104 | PHGDH | Arina Puzriakova Classified gene: PHGDH as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.104 | PHGDH | Arina Puzriakova Gene: phgdh has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.103 | MVK | Arina Puzriakova Classified gene: MVK as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.103 | MVK | Arina Puzriakova Gene: mvk has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.102 | MUSK | Arina Puzriakova Classified gene: MUSK as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.102 | MUSK | Arina Puzriakova Gene: musk has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.101 | KLHL40 | Arina Puzriakova Classified gene: KLHL40 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.101 | KLHL40 | Arina Puzriakova Gene: klhl40 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.100 | DOK7 | Arina Puzriakova Classified gene: DOK7 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.100 | DOK7 | Arina Puzriakova Gene: dok7 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.99 | COL2A1 | Arina Puzriakova Classified gene: COL2A1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.99 | COL2A1 | Arina Puzriakova Gene: col2a1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.98 | CHRNG | Arina Puzriakova Classified gene: CHRNG as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.98 | CHRNG | Arina Puzriakova Gene: chrng has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.97 | CHRND | Arina Puzriakova Classified gene: CHRND as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.97 | CHRND | Arina Puzriakova Gene: chrnd has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.96 | CHRNA1 | Arina Puzriakova Classified gene: CHRNA1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal hydrops v1.96 | CHRNA1 | Arina Puzriakova Gene: chrna1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.26 | EGR2 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 2 unrelated families reported in literature with biallelic EGR2 missense variants, as well as 1 case reported with a homozygous deletion of the EGR2 enhancer, where probands presented with a congenital neuropathy. The more common dominant CMT disease is caused by variants within three-ZNF DNA-binding domains of EGR2; the recessive variants are the only ones reported outside of that domain (PMID: 40262821 Cavalcanti et al., 2025). EGR2 knockout mouse models support the association, as they display disrupted hindbrain segmentation and development (phenotype not seen in het knockouts). Hence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are 2 unrelated families reported in literature with biallelic EGR2 missense variants, as well as 1 case reported with a homozygous deletion of the EGR2 enhancer, where probands presented with a congenital neuropathy. The more common dominant CMT disease is caused by variants within three-ZNF DNA-binding domains of EGR2; the recessive variants are the only ones reported outside of that domain (PMID: 40262821 Cavalcanti et al., 2025). EGR2 knockout mouse models support the association, as mutant mice display disrupted hindbrain segmentation and development (phenotype not seen in het knockouts). Hence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.26 | EGR2 | Ida Ertmanska commented on gene: EGR2: Comment on mode of inheritance: There are 2 unrelated families reported in literature with biallelic EGR2 missense variants, as well as 1 case reported with a homozygous deletion of the EGR2 enhancer, where probands presented with a congenital neuropathy. The more common dominant CMT disease is caused by variants within three-ZNF DNA-binding domains of EGR2; the recessive variants are the only ones reported outside of that domain (PMID: 40262821 Cavalcanti et al., 2025). EGR2 knockout mouse models support the association, as they display disrupted hindbrain segmentation and development (phenotype not seen in het knockouts). Hence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.26 | EGR2 | Ida Ertmanska Phenotypes for gene: EGR2 were changed from Charcot-Marie-Tooth, Type 1; Charcot Marie Tooth disease, type 1D, 607678 to Charcot-Marie-Tooth disease, type 1D, MIM:607678; Dejerine-Sottas disease, MIM:145900; Hypomyelinating neuropathy, congenital, 1, MIM:605253 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.25 | EGR2 | Ida Ertmanska Publications for gene: EGR2 were set to 9537424 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.24 | EGR2 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: EGR2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.24 | EGR2 |
Ida Ertmanska changed review comment from: PMID: 32896048 Lupo et al., 2020 3 affected sibs with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. All 3 individuals were homozygous for the c.791C>T; p.P264L variant in EGR2. Variant not present in gnomAD v4. Consanguineous parents (confirmed het) and wt/het sibs unaffected. PMID: 9537424 Warner et al., 1998 Study included 94 neuropathy patients. Only exons of EGR2 were sequenced. Family HOU336 - 3 male sibs affected by a congenital hypomyelinating neuropathy (CHN). They were floppy at birth, had delayed motor milestones, and walked with crutches at the time of report. The c.803T>A, p.Ile268Asn homozygous missense variant was detected in EGR2 - not reported in gnomAD v4. Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage - phenotype not seen in heterozygous +/- mice. Reports of dominant EGR2-related CMT PMIDs: 9537424; 11523566; 17717711; 20513111; 26204789; 27159987; 30481651; 30843326; 31852952 - copied from ClinGen summary. The association between EGR2 and Semidominant Charcot-Marie-Tooth disease was classified as Definitive (Charcot-Marie-Tooth GCEP, Nov 2021). The gene is associated with AD Charcot-Marie-Tooth disease, type 1D, MIM:607678, AD,AR Dejerine-Sottas disease, MIM:145900, and AD,AR Hypomyelinating neuropathy, congenital, 1, MIM:605253 in OMIM; EGR2-related neuropathy, congenital hypomyelinating (biallelic_autosomal) is ranked Definitive in Gene2Phenotype (accessed 28th July 2026).; to: PMID: 32896048 Lupo et al., 2020 3 affected sibs with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. All 3 individuals were homozygous for the c.791C>T; p.P264L variant in EGR2. Variant not present in gnomAD v4. Consanguineous parents (confirmed het) and wt/het sibs unaffected. PMID: 9537424 Warner et al., 1998 Study included 94 neuropathy patients. Only exons of EGR2 were sequenced. Family HOU336 - 3 male sibs affected by a congenital hypomyelinating neuropathy (CHN). They were floppy at birth, had delayed motor milestones, and walked with crutches at the time of report. The c.803T>A, p.Ile268Asn homozygous missense variant was detected in EGR2 - not reported in gnomAD v4. Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage - phenotype not seen in heterozygous +/- mice. PMID: 22522483 Funalot et al., 2012 Female proband with a congenital amyelinating neuropathy; consanguineous parents of Moroccan origin. She presented with hypotonia at birth, EMG showed absence of peripheral response. No EGR2 immunoreactivity seen in Schwann cells. Detected a homozygous 10.7-kilobase-long deletion encompassing a myelin-specific enhancer of EGR2 in the proband (**non-coding regulatory variant**). Reports of dominant EGR2-related CMT PMIDs: 9537424; 11523566; 17717711; 20513111; 26204789; 27159987; 30481651; 30843326; 31852952 - copied from ClinGen summary. The association between EGR2 and Semidominant Charcot-Marie-Tooth disease was classified as Definitive (Charcot-Marie-Tooth GCEP, Nov 2021). The gene is associated with AD Charcot-Marie-Tooth disease, type 1D, MIM:607678, AD,AR Dejerine-Sottas disease, MIM:145900, and AD,AR Hypomyelinating neuropathy, congenital, 1, MIM:605253 in OMIM; EGR2-related neuropathy, congenital hypomyelinating (biallelic_autosomal) is ranked Definitive in Gene2Phenotype (accessed 28th July 2026). |
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| Hereditary neuropathy or pain disorder v8.24 | EGR2 |
Ida Ertmanska changed review comment from: PMID: 32896048 Lupo et al., 2020 3 affected sibs with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. All 3 individuals were homozygous for the c.791C>T; p.P264L variant in EGR2. Consanguineous parents (confirmed het) and wt/het sibs unaffected. PMID: 9537424 Warner et al., 1998 p.I268N homozygous missense variant detected in EGR2. Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage. The association between EGR2 and Semidominant Charcot-Marie-Tooth disease was classified as Definitive (Charcot-Marie-Tooth GCEP, Nov 2021). The gene is associated with AD Charcot-Marie-Tooth disease, type 1D, MIM:607678, AD,AR Dejerine-Sottas disease, MIM:145900, and AD,AR Hypomyelinating neuropathy, congenital, 1, MIM:605253 in OMIM; EGR2-related neuropathy, congenital hypomyelinating (biallelic_autosomal) is ranked Definitive in Gene2Phenotype (accessed 28th July 2026).; to: PMID: 32896048 Lupo et al., 2020 3 affected sibs with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. All 3 individuals were homozygous for the c.791C>T; p.P264L variant in EGR2. Variant not present in gnomAD v4. Consanguineous parents (confirmed het) and wt/het sibs unaffected. PMID: 9537424 Warner et al., 1998 Study included 94 neuropathy patients. Only exons of EGR2 were sequenced. Family HOU336 - 3 male sibs affected by a congenital hypomyelinating neuropathy (CHN). They were floppy at birth, had delayed motor milestones, and walked with crutches at the time of report. The c.803T>A, p.Ile268Asn homozygous missense variant was detected in EGR2 - not reported in gnomAD v4. Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage - phenotype not seen in heterozygous +/- mice. Reports of dominant EGR2-related CMT PMIDs: 9537424; 11523566; 17717711; 20513111; 26204789; 27159987; 30481651; 30843326; 31852952 - copied from ClinGen summary. The association between EGR2 and Semidominant Charcot-Marie-Tooth disease was classified as Definitive (Charcot-Marie-Tooth GCEP, Nov 2021). The gene is associated with AD Charcot-Marie-Tooth disease, type 1D, MIM:607678, AD,AR Dejerine-Sottas disease, MIM:145900, and AD,AR Hypomyelinating neuropathy, congenital, 1, MIM:605253 in OMIM; EGR2-related neuropathy, congenital hypomyelinating (biallelic_autosomal) is ranked Definitive in Gene2Phenotype (accessed 28th July 2026). |
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| Hereditary neuropathy or pain disorder v8.24 | EGR2 | Ida Ertmanska reviewed gene: EGR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 9537424, 32896048; Phenotypes: Charcot-Marie-Tooth disease, type 1D, MIM:607678, Dejerine-Sottas disease, MIM:145900, Hypomyelinating neuropathy, congenital, 1, MIM:605253; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.33 | GPN2 |
Luke Stuart gene: GPN2 was added gene: GPN2 was added to Monogenic hearing loss. Sources: Literature Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GPN2 were set to 42392036 Phenotypes for gene: GPN2 were set to Sensorineural hearing loss disorder (MONDO:0020678) Review for gene: GPN2 was set to GREEN Added comment: Smith et al. 2026 (PMID 42392036) investigated 3 Perrault syndrome (MIM: 233400, PRLTS1) families via exome sequencing in whom no diagnostic variants were previously found in known PRLTS1 genes or in genes associated with sensorineural hearing loss (SNHL) or primary ovarian insufficiency (POI). Homozygous missense variants in GPN2 were identified in the affected individuals in all three families. Family 1 (PKDF1779): A consanguineous Pakistani family with 10 affected individuals presenting with congenital profound SNHL and POI (all POI diagnosed at <=20 years of age where known). Homozygous GPN2 c.363C>A p.(His121Gln) segregated with disease in all affected individuals (all 10 had profound congenital SNHL); the variant was noted absent from gnomAD v4.1. Family F2 (Irish) comprised two affected sisters with bilateral profound SNHL, POI, and cerebellar ataxia. Both were homozygous for GPN2 c.664A>G p.(Asn222Asp). Brain imaging revealed cerebellar atrophy in both. Family F3 (Australian of Irish ancestry), comprised one affected female proband presenting with profound SNHL, primary amenorrhea, and mild intellectual disability. Homozygous GPN2 c.664A>G p.(Asn222Asp), was identified. Haplotype analysis in the affected members of families F2 and F3 revealed a shared homozygous region of 662 kb indicative of a shared ancestor. The p.(Asn222Asp) variant was noted to be rare in gnomADv4.1 (0.0003763) with no homozygous occurrences. No additional candidate variants in known PRLTS1 genes or genes associated with SNHL or POI were identified. Consistent with other PRLTS1 genes, Gpn2 mRNA was detected in spiral ganglion neurons (SGNs), auditory hair cells, and supporting cells in the mouse inner ear. Conclusions: 13 probands with profound congenital SNHL (n =12), perinatal SNHL (n =1) from 3 kindreds. mRNA expression studies showed high expression in relevant inner-ear structures. No contradictory evidence found. There is sufficient evidence for this gene be promoted to green rating at the next GMS panel update. Sources: Literature |
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| Early onset or syndromic epilepsy v9.46 | DNM1 | Ida Ertmanska commented on gene: DNM1: Comment on mode of inheritance: 'Dominant-negative' heterozygous variants in DNM1 are a known cause of a dominant developmental and epileptic encephalopathy. There are now more than 3 unrelated individuals reported in literature with biallelic LoF DNM1 variants and a recessive Developmental and epileptic encephalopathy. Hence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.46 | DNM1 | Ida Ertmanska Publications for gene: DNM1 were set to 25262651; 27066543; 33372033; 34172529; 36413998 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.45 | DNM1 |
Ida Ertmanska Tag watchlist_moi was removed from gene: DNM1. Tag Q3_26_MOI tag was added to gene: DNM1. |
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| Early onset or syndromic epilepsy v9.45 | DNM1 | Ida Ertmanska reviewed gene: DNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34172529, 36413998, 36553519, 37900685, 41340537; Phenotypes: Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352, developmental and epileptic encephalopathy, 31B, MONDO:0957248, Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346, developmental and epileptic encephalopathy, 31A, MONDO:0014598, DNM1 early infantile epileptic encephalopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.71 | DNM1 |
Ida Ertmanska changed review comment from: BIALLELIC CASES: PMID: 41340537 Drackley et al., 2026 24mo female proband with early infantile developmental and epileptic encephalopathy, including a burst suppression pattern with diffuse slowing on interictal EEG, probable tonic seizures, and profound developmental delay, as well as cerebral atrophy, hypotonia, and arthrogryposis. No head circumference measures given. NGS detected comp het DNM1 variants c.194C>A, p.Thr65Asn (de novo) and c.850C>T p.Gln284* (maternally inherited, mother unaffected). PMID: 37900685 Afsar et al., 2023 Report of a consanguineous Pakistani family. Male proband presented with a neurodevelopmental disorder, mild microcephaly (head circumference: 48.9 cm <1 percentile (−2.8 SD)), moderate to severe ID, speech issues, seizures, epileptic encephalopathy, and hypotonia. WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene. PMID: 36553519 AlTassan et al., 2022 Female proband presented with facial dysmorphism, global developmental delay, seizure disorder, and nystagmus. Head circumference 46 cm (25th percentile) at 18 months. Parents are consanguineous, Arab ancestry. Clinical WES revealed a homozygous deletion in DNM1 (NM_001288739.1: c.350del, p.Pro117Argfs*14). PMID: 34172529 Yigit et al., 2022 Report of 2 families, probands affected by DEE. WES detected homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene. F1 - Lebanese, consanguineous. Female proband presented with multifocal clonic seizures at 15 weeks. At 5yrs, her body weight was 14.35 kg (−2.1 SD); length was 99 cm (−2.4 SD); and OFC was 45.8 cm (−4.4 SD). Lack of verbal understanding and no speech development were noted. F2 - Arab origins, consanguineous. Female proband presented with infantile spasms (onset around 6mo), severe GDD. At 2 years, she presented with microcephaly, visual disturbance and generalised muscular hypotonia. Mild bilateral optic atrophy observed at 3yrs. At 3yrs 8 mo her weight was 10 kg (−3.7 SD); length was 88 cm (−3.1 SD); and OFC was 45 cm (−4.5 SD). MONOALLELIC CASES: PMID: 36413998 Parthasarathy et al., 2022 Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A, 3 individuals harboured p.Arg399Trp, p.Gly401Asp, and p.Pro405Leu missense variants. Importantly, exon 10 is alternatively spliced, with predominantly exon 10a isoform expressed in the brain. Thus, variants in exon 10a result in a more severe phenotype than in exon 10b. Variant p.Pro405Leu, which was the only variant affecting exon 10b isoform, resulted in a less severe neurological presentation (mild DD versus profound DD in all other patients in the cohort).; to: BIALLELIC CASES: PMID: 41340537 Drackley et al., 2026 24mo female proband with early infantile developmental and epileptic encephalopathy, including a burst suppression pattern with diffuse slowing on interictal EEG, probable tonic seizures, and profound developmental delay, as well as cerebral atrophy, hypotonia, and arthrogryposis. No head circumference measures given. NGS detected comp het DNM1 variants c.194C>A, p.Thr65Asn (de novo) and c.850C>T p.Gln284* (maternally inherited, mother unaffected). PMID: 37900685 Afsar et al., 2023 Report of a consanguineous Pakistani family. Male proband presented with a neurodevelopmental disorder, mild microcephaly (head circumference: 48.9 cm <1 percentile (−2.8 SD)), moderate to severe ID, speech issues, seizures, epileptic encephalopathy, and hypotonia. WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene. PMID: 36553519 AlTassan et al., 2022 Female proband presented with facial dysmorphism, global developmental delay, seizure disorder, and nystagmus. Head circumference 46 cm (25th percentile) at 18 months. Parents are consanguineous, Arab ancestry. Clinical WES revealed a homozygous deletion in DNM1 (NM_001288739.1: c.350del, p.Pro117Argfs*14). PMID: 34172529 Yigit et al., 2022 Report of 2 families, probands affected by DEE. WES detected homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene. F1 - Lebanese, consanguineous. Female proband presented with multifocal clonic seizures at 15 weeks. At 5yrs, her body weight was 14.35 kg (−2.1 SD); length was 99 cm (−2.4 SD); and OFC was 45.8 cm (−4.4 SD). Lack of verbal understanding and no speech development were noted. F2 - Arab origins, consanguineous. Female proband presented with infantile spasms (onset around 6mo), severe GDD. At 2 years, she presented with microcephaly, visual disturbance and generalised muscular hypotonia. Mild bilateral optic atrophy observed at 3yrs. At 3yrs 8 mo her weight was 10 kg (−3.7 SD); length was 88 cm (−3.1 SD); and OFC was 45 cm (−4.5 SD). MONOALLELIC CASES: PMID: 36413998 Parthasarathy et al., 2022 Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A, 3 individuals harboured p.Arg399Trp, p.Gly401Asp, and p.Pro405Leu missense variants. Importantly, exon 10 is alternatively spliced, with predominantly exon 10a isoform expressed in the brain. Thus, variants in exon 10a result in a more severe phenotype than in exon 10b. Variant p.Pro405Leu, which was the only variant affecting exon 10b isoform, resulted in a less severe neurological presentation (mild DD versus profound DD in all other patients in the cohort). DNM1 is associated with both AD and AR Developmental and epileptic encephalopathy entities in OMIM (accessed 28th July 2026). The recessive association is classified as Moderate, while dominant disease link is Definitive in ClinGen (Epilepsy GCEP, Feb 2024). |
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| Intellectual disability v10.71 | DNM1 | Ida Ertmanska commented on gene: DNM1: Comment on mode of inheritance: 'Dominant-negative' heterozygous variants in DNM1 are a known cause of a dominant developmental and epileptic encephalopathy. There are now more than 3 unrelated individuals reported in literature with biallelic LoF DNM1 variants and a recessive Developmental and epileptic encephalopathy. Hence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.45 | DNM1 | Ida Ertmanska Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352; developmental and epileptic encephalopathy, 31B, MONDO:0957248; Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346; developmental and epileptic encephalopathy, 31A, MONDO:0014598; DNM1 early infantile epileptic encephalopathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.71 | DNM1 | Ida Ertmanska Phenotypes for gene: DNM1 were changed from Developmental and epileptic encephalopathy 31, OMIM:616346 to Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352; developmental and epileptic encephalopathy, 31B, MONDO:0957248; Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346; developmental and epileptic encephalopathy, 31A, MONDO:0014598; DNM1 early infantile epileptic encephalopathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.70 | DNM1 | Ida Ertmanska Publications for gene: DNM1 were set to 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | DNM1 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: DNM1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | DNM1 | Ida Ertmanska reviewed gene: DNM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34172529, 36413998, 36553519, 37900685, 41340537; Phenotypes: Developmental and epileptic encephalopathy 31B, autosomal recessive, OMIM:620352, developmental and epileptic encephalopathy, 31B, MONDO:0957248, Developmental and epileptic encephalopathy 31A, autosomal dominant, OMIM:616346, developmental and epileptic encephalopathy, 31A, MONDO:0014598, DNM1 early infantile epileptic encephalopathy; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | KDM5B |
Ida Ertmanska changed review comment from: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).; to: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Method: exome seq. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026). |
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| Intellectual disability v10.69 | KDM5B | Ida Ertmanska edited their review of gene: KDM5B: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | KDM5B |
Ida Ertmanska changed review comment from: PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026).; to: PMID: 40657596 Sabetfakhri et al., 2025 Report of a de novo HET PTV (NM_006618.5 c.1708 C>T; p.R570X) in KDM5B in an 18-year-old Caucasian female patient with ASD, who then developed OCD. WISC-V Full Scale Intelligence Quotient (FSIQ) score was 73 at 15yo - borderline ID. PMID: 39202393 Borroto et al., 2024 Study of 21 unrelated individuals with KDM5B variants (19 with a dominant het variant, and 2 with comp het biallelic variants). 16/19 dominant variants were confirmed to be de novo, 2 were inherited from an affected parent (2 unique frameshift variants), and 1 unknown. In the 2 biallelic cases, 3/4 variants were inherited from unaffected parents (missense and nonsense), and a stop gain variant arose de novo. Mix of missense, splicing, frameshift and stop-gain variants. Clinical details of dominant cases: 7/13 had speech delay, 8/15 had ID (1 mild, 4 moderate, and 3 with severe ID). The 2 recessive cases had mild ID. Facial dysmorphism was also common (seen in 13/19 dominant and 1 biallelic case). Overgrowth features were fairly common, with macrocephaly (6/13), obesity (10/16), and heights above the 90th percentile (7/17) noted. Together with 6 previously reported cases, authors summarise that around 80% of dominant cases presented with DD, ID, or both. Across 10 total biallelic cases reported, 100% had ID or DD. PMID: 37231097 Chen et al., 2023 Large scale analysis. Authors pose that KDM5B gene dosage determines clinical phenotype - HET PTV carriers show an attenuated phenotype relative to individuals with HOM KDM5B LoF mutations. Educational attainment (EDU) and verbal-numerical reasoning (VNR) were on average lower in KDM5B PTV carriers (n = 204 for EDU and n = 79 for VNR) than in noncarriers (standardized, residualized phenotype mean = −0.3669 for EDU and −0.5387 for VNR). This was supported by studies in mice, where both cognitive and skeletal features (e.g., changes in craniofacial dimensions or transitional vertebrae) were intermediate in the het mice, compared to a severe presentation of homozygous knockout mice. The association between AR Intellectual Disability and KDM5B was classified as Moderate in ClinGen (Intellectual Disability and Autism GCEP, Mar 2022) - AD inheritance not curated. The gene is only associated with Intellectual developmental disorder, autosomal recessive 65, OMIM:618109 in OMIM (Accessed 28th July 2026). |
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| Intellectual disability v10.69 | KDM5B | Ida Ertmanska edited their review of gene: KDM5B: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.24 | APOPT1 | Achchuthan Shanmugasundram commented on gene: APOPT1: PMID:25175347 (2014) reported a total of six patients from five unrelated families identified with biallelic variants in APOPT1 gene. There were six different variants identified from these patients and all but one were homozygous, and one individual had compound heterozygous variants. The clinical features of all six patients varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. Peripheral neuropathy was reported in two patients | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | KDM5B | Ida Ertmanska reviewed gene: KDM5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 37231097, 39202393; Phenotypes: Intellectual developmental disorder, autosomal recessive 65, OMIM:618109; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Neurodegenerative disorders, adult onset v9.3 | FIG4 |
Ida Ertmanska changed review comment from: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).; to: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022). |
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| Neurodegenerative disorders, adult onset v9.3 | FIG4 |
Ida Ertmanska changed review comment from: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS; c.2158G>T [p.E720X] - classified LP. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022).; to: PMID: 38695966 Ferreira et al., 2024 Case report of a 34yo European male with ALS and a het FIG4:c.122T>C, p.Ile41Thr variant - fairly high gnomAD freq in the European population = 0.001949 (includes 2 homozygotes); known Pathogenic variant in recessive CMT cases. PMID: 36090855 Yilihamu et al., 2022 Het FIG4 c.350dupC, p.Asp118GlyfsTer9 variant reported in a 55yo Chinese patient with rapidly progressive ALS. PMID: 35021275 Liu et al., 2021 Cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. Only sequenced FIG4. 2 SALS patients had het FIG4 variants: c.352G>T [p.D118Y] - labelled VUS, 1 allele in gnomAD v4; c.2158G>T [p.E720X] - classified LP, not in gnomAD v4. PMID: 29464931 Bertolin et al., 2018 Case report of a 27yo Caucasian female. EMG and NCS did not show peripheral neuropathy or denervation signs. Spinal cord MRI was normal, while brain MRI showed cortical and CC atrophy. She was diagnosed with juvenile ALS. Genetic testing detected comp het FIG4 variants c.122T>C, p.Ile41Thr & c.1667C>T, p.Thr556Ile. PMID: 28051077 Osmanovic et al., 2017 German family with 2 individuals affected by ALS. Index patient and his father harboured FIG4:c.759delG, p.(F254Sfs*8). Index patient had ALS onset at 40yrs, but father was unaffected at 75yrs. Paternal great aunt affected but not genotyped (deceased). No good evidence of segregation. Method: WES. 5 sporadic patients also detected with het missense variants in FIG4: c.122T>C, p.(I41T); c.1619C>T, p.(T540I); c.919G>A, p.(D307N); c.1940A>G, p.(Y647C); c.2558C>T, p.(S853L). FIG4 is associated with AD Amyotrophic lateral sclerosis 11, MIM:612577 in OMIM (accessed 28th Jul 2026). The association between FIG4 and AD amyotrophic lateral sclerosis type 11 was classified as Limited in ClinGen (Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP, Aug 2022). |
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| Neurodegenerative disorders, adult onset v9.3 | FIG4 | Ida Ertmanska reviewed gene: FIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28051077, 29464931, 35021275, 36090855, 38695966; Phenotypes: Amyotrophic lateral sclerosis 11, OMIM:612577; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.24 | APOPT1 | Achchuthan Shanmugasundram reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347, 38098475; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061, mitochondrial complex IV deficiency, nuclear type 17, MONDO:0033652, peripheral neuropathy, MONDO:0005244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.24 | FAT3 | Achchuthan Shanmugasundram Classified gene: FAT3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.24 | FAT3 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there is sufficient evidence available (three unrelated cases and functional evidence) for the association of FAT3 with neuropathy. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.24 | FAT3 | Achchuthan Shanmugasundram Gene: fat3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.23 | FAT3 | Achchuthan Shanmugasundram Phenotypes for gene: FAT3 were changed from axonal sensory and motor peripheral neuropathy; cranial neuropathy; scoliosis; respiratory failure; pseudoobstruction to peripheral neuropathy, MONDO:0005244 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.22 | FAT3 | Achchuthan Shanmugasundram Publications for gene: FAT3 were set to PMID: 41937739 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.21 | FAT3 |
Achchuthan Shanmugasundram Tag Q3_26_NHS_review tag was added to gene: FAT3. Tag Q3_26_promote_green tag was added to gene: FAT3. |
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| Hereditary neuropathy or pain disorder v8.21 | FAT3 | Achchuthan Shanmugasundram reviewed gene: FAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 41937739; Phenotypes: peripheral neuropathy, MONDO:0005244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.13 | NUP205 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: NUP205. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.13 | NUP205 | Achchuthan Shanmugasundram Classified gene: NUP205 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.13 | NUP205 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases and functional evidence reported in support of the association of NUP205 with nephrotic syndrome. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.13 | NUP205 | Achchuthan Shanmugasundram Gene: nup205 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.12 | NUP205 | Achchuthan Shanmugasundram Phenotypes for gene: NUP205 were changed from ?Nephrotic syndrome, type 13 #616893 to ?Nephrotic syndrome, type 13 , OMIM:616893; nephrotic syndrome, type 13, MONDO:0014818 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.11 | NUP205 | Achchuthan Shanmugasundram Publications for gene: NUP205 were set to 26878725 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.10 | NUP205 | Achchuthan Shanmugasundram Mode of inheritance for gene: NUP205 was changed from to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.9 | NUP205 |
Achchuthan Shanmugasundram changed review comment from: PMID:26878725 (2016) reported a homozygous missense variant in the nucleoporin NUP205 gene (p.Phe1995Ser) in two siblings of Turkish descent with early-onset steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS), identified via genetic mapping and whole exome sequencing. PMID:29127259 (2018) reported the same family from PMID:26878725 (2016), and an unrelated patient of Arabic descent with SRNS and FSGS and identified with homozygous p.Cys1032Tyr variant. PMID:36245711 (2022) reported a homozygous variant in NUP205 gene (p.Leu1110Pro) identified via trio exome sequencing in an Iranian paediatric patient with SRNS (age of onset - 12 months). PMID:33065118 (2021) reported supportive functional studies from Xenopus knockout which demonstrated abnormal left right patterning and dysfunctional pronephric development.; to: PMID:26878725 (2016) reported a homozygous missense variant in the nucleoporin NUP205 gene (p.Phe1995Ser) in two siblings of Turkish descent with early-onset steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS), identified via genetic mapping and whole exome sequencing. PMID:29127259 (2018) reported the same family from PMID:26878725 (2016), and an unrelated patient of Arabic descent with SRNS and FSGS and identified with homozygous p.Cys1032Tyr variant. PMID:36245711 (2022) reported a homozygous variant in NUP205 gene (p.Leu1110Pro) identified via trio exome sequencing in an Iranian paediatric patient with SRNS (age of onset - 12 months). PMID:33065118 (2021) reported supportive functional studies from Xenopus knockout which demonstrated abnormal left right patterning and dysfunctional pronephric development. PMID:37565816 (2023) reported NUP205 as a key inner‑ring nucleoporin that physically associates with YAP/TAZ and is required for their nuclear import, TEAD‑mediated transcription, and podocyte survival under stress. Functionally, NUP205 knockdown reduces nuclear YAP/TAZ, down‑regulates canonical Hippo target genes, and increases podocyte death, providing strong mechanistic support that NUP205 dysfunction can drive glomerular disease. This gene has tentatively been associated with MIM #616893 in OMIM (?Nephrotic syndrome, type 13) - last accessed 27 July 2026. It is associated with nephrotic syndrome, type 13 (MONDO:0014818) with 'limited' rating by Glomerulopathy GCEP in ClinGen (https://search.clinicalgenome.org/CCID:009001). |
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| Proteinuric renal disease v6.9 | NUP205 | Achchuthan Shanmugasundram edited their review of gene: NUP205: Changed rating: GREEN; Changed publications to: 26878725, 29127259, 33065118, 36245711, 37565816; Changed phenotypes to: ?Nephrotic syndrome, type 13 , OMIM:616893, nephrotic syndrome, type 13, MONDO:0014818; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.9 | NUP205 | Achchuthan Shanmugasundram reviewed gene: NUP205: Rating: ; Mode of pathogenicity: None; Publications: 26878725, 29127259, 33065118, 36245711; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital hyperinsulinism v3.9 | CACNA1C | Arina Puzriakova Tag Q3_26_expert_review tag was added to gene: CACNA1C. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.21 | LAS1L |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance. Hence, this gene should be rated amber with the current evidence. However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.; to: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance. Hence, this gene should be rated amber with the current evidence. However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence. |
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| Hereditary neuropathy or pain disorder v8.21 | LAS1L |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. The main phenotype reported for this gene is syndromic intellectual disability (Wilson-Turner syndrome, MIM# 309585). Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance. Hence, this gene should be rated amber with the current evidence. However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.; to: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance. Hence, this gene should be rated amber with the current evidence. However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence. |
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| Hereditary neuropathy or pain disorder v8.21 | LAS1L |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. The main phenotype reported for this gene is syndromic intellectual disability (Wilson-Turner syndrome, MIM# 309585). Hence, this gene should be rated amber with the current evidence. However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence.; to: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. The main phenotype reported for this gene is syndromic intellectual disability (Wilson-Turner syndrome, MIM# 309585). Karen Stals reported in her review that there is an additional case in Exeter, but the variant is of uncertain significance. Hence, this gene should be rated amber with the current evidence. However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence. |
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| Hereditary neuropathy or pain disorder v8.21 | LAS1L |
Achchuthan Shanmugasundram changed review comment from: LAS1L is associated with Wilson-Turner syndrome, which is a syndromic intellectual developmental disorder in OMIM (MIM #309585, last accessed 26 July 2026). PMID:24647030 (2014) reported the identification of a de novo hemizygous missense variant (c.1430G>A, p.Ser477Asn) in a male neonate proband with fatal congenital spinal muscular atrophy with respiratory distress (SMARD)-like motor neuron disease. There is supporting evidence available from zebrafish rescue experiments. PMID:35627110 (2022) reported the identification of a novel hemizygous synonymous variant in the LAS1L gene inherited from an unaffected mother (c.846G>C, p.Thr282=) in an eighteen-month old male patient with a SMARD phenotype. Maternal fibroblasts showed no coding-region transcript, suggesting skewed X-inactivation silencing the variant allele in her cells.; to: LAS1L is associated with Wilson-Turner syndrome, which is a syndromic intellectual developmental disorder in OMIM (MIM #309585, last accessed 26 July 2026). PMID:24647030 (2014) reported the identification of a de novo hemizygous missense variant (c.1430G>A, p.Ser477Asn) in a male neonate proband with fatal congenital spinal muscular atrophy with respiratory distress (SMARD)-like motor neuron disease. There is supporting evidence available from zebrafish rescue experiments. PMID:35627110 (2022) reported the identification of a novel hemizygous synonymous variant in the LAS1L gene inherited from an unaffected mother (c.846G>C, p.Thr282=) in an eighteen-month old male patient with a SMARD phenotype. Maternal fibroblasts showed no coding-region transcript, suggesting skewed X-inactivation silencing the variant allele in her cells. |
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| Hereditary neuropathy or pain disorder v8.21 | LAS1L | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: LAS1L. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.21 | LAS1L | Achchuthan Shanmugasundram Classified gene: LAS1L as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.21 | LAS1L |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases and some functional evidence reported in support of the association of LAS1L gene with SMARD-like phenotype. The main phenotype reported for this gene is syndromic intellectual disability (Wilson-Turner syndrome, MIM# 309585). Hence, this gene should be rated amber with the current evidence. However, 'watchlist' tag added so that this gene will be reviewed in light of new evidence. |
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| Hereditary neuropathy or pain disorder v8.21 | LAS1L | Achchuthan Shanmugasundram Gene: las1l has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.20 | LAS1L | Achchuthan Shanmugasundram Phenotypes for gene: LAS1L were changed from to Wilson-Turner syndrome, OMIM:309585; Spinal muscular atrophy with respiratory distress (SMARD)-like motor neuron disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.19 | LAS1L | Achchuthan Shanmugasundram edited their review of gene: LAS1L: Changed phenotypes to: Wilson-Turner syndrome, OMIM:309585, Spinal muscular atrophy with respiratory distress (SMARD)-like motor neuron disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.19 | LAS1L | Achchuthan Shanmugasundram Publications for gene: LAS1L were set to 24647030 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.18 | LAS1L | Achchuthan Shanmugasundram Mode of inheritance for gene: LAS1L was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.17 | LAS1L | Achchuthan Shanmugasundram reviewed gene: LAS1L: Rating: AMBER; Mode of pathogenicity: None; Publications: 24647030, 35627110; Phenotypes: Wilson-Turner syndrome, OMIM:309585, motor neuron disorder, MONDO:0020128; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.44 | PRRT2 | Ida Ertmanska Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis; Episodic kinesigenic dyskinesia 1; Seizures, benign familial infantile, 2; BENIGN FAMILIAL INFANTILE EPILEPSY AND INFANTILE CONVULSIONS WITH CHOREOATHETOSIS SYNDROME to PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Convulsions, familial infantile, with paroxysmal choreoathetosis; Episodic kinesigenic dyskinesia 1; Seizures, benign familial infantile, 2; BENIGN FAMILIAL INFANTILE EPILEPSY AND INFANTILE CONVULSIONS WITH CHOREOATHETOSIS SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.43 | PRRT2 | Ida Ertmanska Publications for gene: PRRT2 were set to Wan et al (2011) Brain 134: 3493_3501; Chen et al (2011) Nature Genet 43(12): 1252-1256; Heron et al (2012) Am J Hum Genet 90: 152_160 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.42 | PRRT2 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: PRRT2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.42 | PRRT2 | Ida Ertmanska commented on gene: PRRT2: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' and benign familial infantile seizures - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Epilepsy is the most consistent feature in reported patients. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.42 | PRRT2 | Ida Ertmanska reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23126439, 25595153, 31193310, 36247910, 38316952; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.6 | PRRT2 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.7 | PRRT2 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.7 | PRRT2 | Ida Ertmanska Phenotypes for gene: PRRT2 were changed from Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066; Episodic kinesigenic dyskinesia 1, 128200; dystonia and occasionally hemiplegic migraine and epilepsy; Paroxysmal kinesigenic choreoathetosis (PKD1) and infantile convulsions; episodic kinesigenic dyskinesia to PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066; Episodic kinesigenic dyskinesia 1, 128200; dystonia and occasionally hemiplegic migraine and epilepsy; Paroxysmal kinesigenic choreoathetosis (PKD1) and infantile convulsions; episodic kinesigenic dyskinesia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.6 | PRRT2 | Ida Ertmanska Publications for gene: PRRT2 were set to 22744660; 20301334; 22399141; 22120146; 22101681 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.5 | PRRT2 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: PRRT2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.6 | PRRT2 | Ida Ertmanska Phenotypes for gene: PRRT2 were changed from Seizures, benign familial infantile, 2, 605751; dystonia and occasionally hemiplegic migraine and epilepsy; Episodic kinesigenic dyskinesia 1, 128200; Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066 to PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Seizures, benign familial infantile, 2, 605751; dystonia and occasionally hemiplegic migraine and epilepsy; Episodic kinesigenic dyskinesia 1, 128200; Convulsions, familial infantile, with paroxysmal choreoathetosis, 602066 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.5 | PRRT2 | Ida Ertmanska Publications for gene: PRRT2 were set to 22744660; 22101681; 22120146; 22399141 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.5 | PRRT2 | Ida Ertmanska commented on gene: PRRT2: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, childhood onset v8.5 | PRRT2 | Ida Ertmanska reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23126439, 25595153, 31193310, 36247910, 38316952; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.4 | PRRT2 | Ida Ertmanska commented on gene: PRRT2: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset epilepsy, dyskinesia, and episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.4 | PRRT2 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: PRRT2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paroxysmal central nervous system disorders v4.4 | PRRT2 | Ida Ertmanska reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23126439, 25595153, 31193310, 36247910, 38316952; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.13 | PRRT2 | Ida Ertmanska changed review comment from: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset episodic ataxia. Cerebellar atrophy was also confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset episodic ataxia. Additionally, cerebellar atrophy was confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.13 | PRRT2 | Ida Ertmanska commented on gene: PRRT2: Comment on mode of inheritance: Heterozygous PRRT2 variants are a well known cause of 'Convulsions, familial infantile, with paroxysmal choreoathetosis' - most commonly the c.649dupC variant. There are also several individuals reported in literature with biallelic PRRT2 variants and a more severe neurologic presentation, including childhood-onset episodic ataxia. Cerebellar atrophy was also confirmed on MRI in 2 cases. Hence, the MOI should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.13 | PRRT2 | Ida Ertmanska Publications for gene: PRRT2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.12 | PRRT2 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: PRRT2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.12 | PRRT2 | Ida Ertmanska reviewed gene: PRRT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23126439, 25595153, 31193310, 36247910, 38316952; Phenotypes: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PRRT2 | Ida Ertmanska edited their review of gene: PRRT2: Changed phenotypes to: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066, PRRT2-associated paroxysmal movement disorder, MONDO:0100556 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PRRT2 | Ida Ertmanska commented on gene: PRRT2: Comment on list classification: While there are a few individuals reported in literature with biallelic PRRT2 variants and severe intellectual disability (e.g., PMID: 36247910), most patients have normal cognition. More consistent features include early onset epilepsy, episodic ataxia, and dyskinesia. Hence, this gene should remain Amber on Intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PRRT2 | Ida Ertmanska edited their review of gene: PRRT2: Changed publications to: 23126439, 25595153, 31193310, 36247910, 38316952; Changed phenotypes to: Convulsions, familial infantile, with paroxysmal choreoathetosis, OMIM:602066 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PRRT2 |
Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 31193310 El Achkar et al., 2019 Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs*8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, not cognitive impairment. PMID: 25595153 Delcourt et al., 2015 Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026).; to: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the splice variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 31193310 El Achkar et al., 2019 Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs*8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, no cognitive impairment seen in the proband. PMID: 25595153 Delcourt et al., 2015 Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases. PMID: 23126439 Labate et al., 2012 Homozygous c.649dupC mutation in PRRT2 detected in 2 sibs from a consanguineous Italian family resulted in ID, episodic ataxia, and absences. 4 other affected family members, het for the same mutation, presented only with benign familial infantile seizures / familial paroxysmal kinesigenic dystonia. DOI: 10.1055/s-0045-1810051 Eshrif & Adofani, 2025 Case report of a family with epilepsy and dyskinesia due to a homozygous PRRT2 variant c.649dup, p.(Arg217Profs8). 3 sibs affected, all 3 presented with focal seizures at 3-8 months old, and 2/3 individuals also had dyskinesia. Family history not discussed, parents assumed to be unaffected from the pedigree. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026). |
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| Intellectual disability v10.69 | PRRT2 |
Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 25595153 Delcourt et al., 2015 https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.; to: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 31193310 El Achkar et al., 2019 Report of a male patient with a severe phenotype including infantile epilepsy with status epilepticus, paroxysmal dyskinesia and episodic ataxia. He harboured comp het PRRT2 variants c.649dupC, p.Arg217Profs*8 (maternal) and c.916G>A, p.Ala306Thr (paternal). Mother and brother het for c.649dupC were asymptomatic. On father's side, there is family history of episodic confusion and episodic hemiparesis (only father genotyped). Normal development noted at 5 years old, not cognitive impairment. PMID: 25595153 Delcourt et al., 2015 Report of 5 patients with biallelic PRRT2 variants: 3 homozygous for c.649dupC, P1 was comp het for c.649dupC and a de novo whole PRRT2 gene deletion, and P5 was homozygous for PRRT2 c.913G>A, p.Gly305Arg. While 4 individuals had some learning difficulties and ADHD, their cognition was normal. All 5 patients had seizures with onset before 6 months of life; episodic ataxia was present in patients 1-4 (not normally seen in heterozygous individuals); cerebellar atrophy was seen on MRI in 2 cases. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. The PRRT2-related neurodevelopmental and movement disorder with or without seizures (biallelic_autosomal) entry has Moderate confidence in G2P. PRRT2 is not yet associated with a recessive disorder in OMIM or ClinGen (accessed 27th July 2026). |
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| Hereditary neuropathy v1.513 | POLR3A | Arina Puzriakova Phenotypes for gene: POLR3A were changed from Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, 607694; Adolescent onset progressive spastic ataxia, tremor, involvement of central sensory tracts, dental complications; Bilateral hyperintensities on MRI from the superior cerebellar peduncle to the dentate nucleus / midbrain to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694; leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897; peripheral neuropathy, MONDO:0005244 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy v1.512 | POLR3A | Arina Puzriakova Publications for gene: POLR3A were set to 28459997 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy v1.511 | POLR3A | Arina Puzriakova Added comment: Comment on mode of inheritance: There are 8 unrelated families reported with monoallelic variants and early-onset peripheral neuropathy. Hence, MOI was updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy v1.511 | POLR3A | Arina Puzriakova Mode of inheritance for gene: POLR3A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy v1.510 | POLR3A | Arina Puzriakova reviewed gene: POLR3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 42260910; Phenotypes: Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694, leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897, peripheral neuropathy, MONDO:0005244; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PRRT2 |
Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.; to: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. Parents were het carriers. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. PMID: 25595153 Delcourt et al., 2015 https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. |
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| Intellectual disability v10.69 | PRRT2 |
Ida Ertmanska changed review comment from: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side. Proband diagnosed with severe ID and ASD. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected.; to: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side (mother het for c.649dupC). Proband diagnosed with severe ID and ASD. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. |
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| Intellectual disability v10.69 | PRRT2 |
Ida Ertmanska changed review comment from: PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side. Proband diagnosed with severe ID and ASD. PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant.; to: PMID: 38316952 Koko et al., 2024 Sudanese family reported with a homozygous PRRT2 variant [NC_000016.10(NM_145239.3):c.-65-1G > A] and self-limited infantile epilepsy. No intellectual disability seen, siblings preformed well in school. The mild presentation of sibs is hypothesised to come from a hypomorphic character of the biallelic PRRT2 variant. PMID: 36247910 Martorell et al., 2022 Report of a female patient, presented with epileptic seizures at 2 months old. She started walking at 18 months, but had a very severe language delay. Episodic ataxia was noted at 2yrs. 2 PRRT2 variants detected in trans: c.649dupC and c.649delC. History of afebrile seizures noted on mother's side. Proband diagnosed with severe ID and ASD. https://doi.org/10.1016/j.mgene.2016.12.005 Kishk et al., 2017 Case report of an Egyptian family - two sibs with Infantile convulsions and choreoathetosis and a homozygous PRRT2 variant c.649dupC. No physical or cognitive disabilities noted. Het parents unaffected. |
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| Intellectual disability v10.69 | PRRT2 | Ida Ertmanska reviewed gene: PRRT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36247910, 38316952; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal tubulopathies v6.9 | TFCP2L1 | Ida Ertmanska Classified gene: TFCP2L1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal tubulopathies v6.9 | TFCP2L1 | Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harbouring biallelic TFCP2L1 variants presented with early-onset kidney dysfunction diagnosed as renal tubulopathy (among other less specific findings). Tfcp2l1-deficient mice showed defects in renal duct maturation. Taken together, there is enough evidence to promote this gene to Green at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal tubulopathies v6.9 | TFCP2L1 | Ida Ertmanska Gene: tfcp2l1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal tubulopathies v6.8 | TFCP2L1 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: TFCP2L1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal tubulopathies v6.8 | TFCP2L1 | Ida Ertmanska edited their review of gene: TFCP2L1: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal tubulopathies v6.8 | TFCP2L1 | Ida Ertmanska edited their review of gene: TFCP2L1: Changed publications to: 17079272, 33097957, 40569305, 42362802 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal tubulopathies v6.8 | TFCP2L1 |
Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026 Family 22 - 2 sibs with exon 1-2 deletion in TFCP2L1; presentation: microcrephaly, CKD (diagnosis of renal tubulopathy), SNHL. Seq method: exome seq. PMID: 40569305 Graña et al., 2025 'Ultra-rare severe kidney dysplasia mimicking salt-wasting tubulopathy associated with TFCP2L1 gene variants' Study described a consanguineous preterm male infant with advanced kidney dysfunction and severe renal salt-wasting, suggestive of Bartter syndrome. Follow-up showed severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. No cataracts or seizures seen in this patient. He was homozygous for TFCP2L1 (NM_014553.3):c.1279 del; p.(Gln427Serfs*18)). Method: WES. PMID: 33097957 Klämbt et al., 2021 Report of a 4yo female patient (B2033-21) from a consanguineous Arabic Yemeni family, harbouring a homozygous TFCP2L1 variant c.869del, p. Ser290Phefs*50. Method: WES. Parents confirmed het. Patient presented with echogenic kindeys and CKD developed before 2 months of age; ESRD age 3.5 years, hypochloremic, hypokalemic alkalosis, small echogenic kidneys. In addition, she had cataracts, seizures, developmental delay, hypotonia. TFCP2L1 is not yet associated with a disease in OMIM, Gene2Phenotype, or ClinGen (accessed 27th July 2026). Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026 Family 22 - 2 sibs with exon 1-2 deletion in TFCP2L1; presentation: microcrephaly, CKD (diagnosis of renal tubulopathy), SNHL. Seq method: exome seq. PMID: 40569305 Graña et al., 2025 'Ultra-rare severe kidney dysplasia mimicking salt-wasting tubulopathy associated with TFCP2L1 gene variants' Study described a consanguineous preterm male infant with advanced kidney dysfunction and severe renal salt-wasting, suggestive of Bartter syndrome. Follow-up showed severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. No cataracts or seizures seen in this patient. He was homozygous for TFCP2L1 (NM_014553.3):c.1279 del; p.(Gln427Serfs*18)). Method: WES. PMID: 33097957 Klämbt et al., 2021 Report of a 4yo female patient (B2033-21) from a consanguineous Arabic Yemeni family, harbouring a homozygous TFCP2L1 variant c.869del, p. Ser290Phefs*50. Method: WES. Parents confirmed het. Patient presented with echogenic kindeys and CKD developed before 2 months of age; ESRD age 3.5 years, hypochloremic, hypokalemic alkalosis, small echogenic kidneys. In addition, she had cataracts, seizures, developmental delay, hypotonia. FUNCTIONAL EVIDENCE: PMID: 17079272 Yamaguchi, Yonemura, & Takada, 2006 TFCP2L1 is required for the maturation of the ducts of the salivary gland and kidney, as it coordinates the expression of several genes that are involved in physiological function and generate the appropriate cellular architecture. In Cp2l1-deficient mice, the expression of genes directly involved in functional maturation of the ducts was specifically reduced in both the salivary gland and kidney. Furthermore, the composition of saliva and urine was abnormal in these mice. Tfcp2l1−/− mice were evaluated for urinary excretion of electrolytes and showed a urinary potassium loss similar to patient B2033-21 in PMID: 33097957. TFCP2L1 is not yet associated with a disease in OMIM, Gene2Phenotype, or ClinGen (accessed 27th July 2026). Sources: Literature |
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| Renal tubulopathies v6.8 | TFCP2L1 |
Ida Ertmanska gene: TFCP2L1 was added gene: TFCP2L1 was added to Renal tubulopathies. Sources: Literature Mode of inheritance for gene: TFCP2L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TFCP2L1 were set to 33097957; 40569305; 42362802 Phenotypes for gene: TFCP2L1 were set to chronic kidney disease, MONDO:0005300; Renal tubular dysfunction, HP:0000124 Review for gene: TFCP2L1 was set to AMBER Added comment: PMID: 42362802 Chaurasia et al., 2026 Family 22 - 2 sibs with exon 1-2 deletion in TFCP2L1; presentation: microcrephaly, CKD (diagnosis of renal tubulopathy), SNHL. Seq method: exome seq. PMID: 40569305 Graña et al., 2025 'Ultra-rare severe kidney dysplasia mimicking salt-wasting tubulopathy associated with TFCP2L1 gene variants' Study described a consanguineous preterm male infant with advanced kidney dysfunction and severe renal salt-wasting, suggestive of Bartter syndrome. Follow-up showed severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. No cataracts or seizures seen in this patient. He was homozygous for TFCP2L1 (NM_014553.3):c.1279 del; p.(Gln427Serfs*18)). Method: WES. PMID: 33097957 Klämbt et al., 2021 Report of a 4yo female patient (B2033-21) from a consanguineous Arabic Yemeni family, harbouring a homozygous TFCP2L1 variant c.869del, p. Ser290Phefs*50. Method: WES. Parents confirmed het. Patient presented with echogenic kindeys and CKD developed before 2 months of age; ESRD age 3.5 years, hypochloremic, hypokalemic alkalosis, small echogenic kidneys. In addition, she had cataracts, seizures, developmental delay, hypotonia. TFCP2L1 is not yet associated with a disease in OMIM, Gene2Phenotype, or ClinGen (accessed 27th July 2026). Sources: Literature |
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| Hereditary neuropathy or pain disorder v8.17 | DHTKD1 | Arina Puzriakova Tag Q3_26_expert_review tag was added to gene: DHTKD1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PDS5B | Achchuthan Shanmugasundram edited their review of gene: PDS5B: Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PDS5B | Achchuthan Shanmugasundram Classified gene: PDS5B as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PDS5B | Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are eight unrelated patients reported with PDS5B variants and variable neurodevelopmental features, intellectual disability was only reported in one. Hence, this gene should be rated red with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.69 | PDS5B | Achchuthan Shanmugasundram Gene: pds5b has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.68 | PDS5B |
Achchuthan Shanmugasundram gene: PDS5B was added gene: PDS5B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PDS5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PDS5B were set to 42431198 Phenotypes for gene: PDS5B were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: PDS5B was set to AMBER Added comment: PMID:42431198 (2026) reported eight unrelated patients with rare heterozygous loss of function variants in PDS5B gene, of which inheritance was de novo in four, unknown in three, and inherited from unaffected parent in one. They presented with variable neurodevelopmental features and intellectual disability was reported only in one. No functional evidence available. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia. Sources: Literature |
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| Intellectual disability v10.67 | PDS5A |
Achchuthan Shanmugasundram changed review comment from: PMID:30158690 (2019) reoported a cohort that had undergone exome sequencing of which one patient with intellectual disability/ developmental delay was identified with a paternally inherited PDS5A variant (p.Glu759Ter) and a de novo ASXL3 variant. PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia. Sources: Literature; to: PMID:30158690 (2019) reoported a cohort that had undergone exome sequencing of which one patient with intellectual disability/ developmental delay was identified with a paternally inherited PDS5A variant (p.Glu759Ter) and a de novo ASXL3 variant. PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients. No functional evidence available. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia. Sources: Literature |
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| Intellectual disability v10.67 | PDS5A | Achchuthan Shanmugasundram Publications for gene: PDS5A were set to 42431198 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.17 | MT-TV | Arina Puzriakova Tag Q3_26_NHS_review tag was added to gene: MT-TV. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.66 | PDS5A |
Achchuthan Shanmugasundram changed review comment from: PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia. Sources: Literature; to: PMID:30158690 (2019) reoported a cohort that had undergone exome sequencing of which one patient with intellectual disability/ developmental delay was identified with a paternally inherited PDS5A variant (p.Glu759Ter) and a de novo ASXL3 variant. PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia. Sources: Literature |
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| Intellectual disability v10.66 | PDS5A | Achchuthan Shanmugasundram edited their review of gene: PDS5A: Changed publications to: 30158690, 42431198 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.66 | PDS5A | Achchuthan Shanmugasundram Classified gene: PDS5A as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.66 | PDS5A |
Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are four unrelated patients reported with only heterozygous variants from PDS5A gene and with intellectual disability/ global developmental delay, the phenotype is not consistent across the eight reported patients with heterozygous PDS5A variants. Hence, the gene should be rated amber with current evidence. The 'watchlist' tag has been added to review the gene upon any new evidence. |
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| Intellectual disability v10.66 | PDS5A | Achchuthan Shanmugasundram Gene: pds5a has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.65 | PDS5A | Achchuthan Shanmugasundram Tag watchlist tag was added to gene: PDS5A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.65 | PDS5A |
Achchuthan Shanmugasundram gene: PDS5A was added gene: PDS5A was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PDS5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PDS5A were set to 42431198 Phenotypes for gene: PDS5A were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: PDS5A was set to AMBER Added comment: PMID:42431198 (2026) reported the identification of heterozygous PDS5A variants in eight unrelated individuals and the inheritance was de novo in four, maternal in one and unknown in three. Patients with variants in PDS5A presented with considerable morbidity, and every patient had neurodevelopmental (e.g., developmental delay, intellectual disability) and/or other neurological features (e.g., epilepsy, hypotonia, abnormal brain imaging). However, these features were variable and less convincing as unified syndromic presentations. Severe intellectual disability was reported in two patients and global developmental delay was reported in two other patients. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with amber rating on the intellectual disability panel of PanelApp Australia. Sources: Literature |
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| Intellectual disability v10.64 | WAPL | Achchuthan Shanmugasundram Classified gene: WAPL as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.64 | WAPL | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of WAPL gene with intellectual disability/ global developmental delay, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.64 | WAPL | Achchuthan Shanmugasundram Gene: wapl has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.63 | WAPL |
Achchuthan Shanmugasundram gene: WAPL was added gene: WAPL was added to Intellectual disability. Sources: Literature Q3_26_promote_green tags were added to gene: WAPL. Mode of inheritance for gene: WAPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WAPL were set to 42431198 Phenotypes for gene: WAPL were set to complex neurodevelopmental disorder, MONDO:0100038 Review for gene: WAPL was set to GREEN Added comment: PMID:42431198 (2026) reported the identification of heterozygous WAPL variants in 27 patients, of which 19 patients had confirmed de novo variants. The WAPL-related disorder was characterised by developmental delay, intellectual disability, and risk of other developmental anomalies. Syndromic intellectual disability was reported in 6 patients and Global developmental delay (GDD) was reported in 10 patients. Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes. Mice with 50% Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen, but associated with green rating on the intellectual disability panel of PanelApp Australia. Sources: Literature |
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| Intellectual disability v10.62 | VPS36 |
Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026). Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5, not assessed in F52), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026). Sources: Literature |
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| Intellectual disability v10.62 | VPS36 | Ida Ertmanska edited their review of gene: VPS36: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.62 | VPS36 | Ida Ertmanska Classified gene: VPS36 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.62 | VPS36 | Ida Ertmanska Added comment: Comment on list classification: 3 unrelated families have been reported with biallelic VPS36 variants and intellectual disability, and developmental delay including motor & speech delay. Hence, this gene can be promoted to Green at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.62 | VPS36 | Ida Ertmanska Gene: vps36 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.61 | VPS36 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: VPS36. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.42 | VPS36 | Ida Ertmanska Classified gene: VPS36 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.42 | VPS36 | Ida Ertmanska Added comment: Comment on list classification: Seizures have been reported in 3 families with biallelic VPS36 variants and seizures. However, two of these families harboured the same variant and shared ancestry was seen in haplotype analysis. Hence, this gene can only be rated Amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.42 | VPS36 | Ida Ertmanska Gene: vps36 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.41 | VPS36 |
Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026). Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6, not in family 52), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026). Sources: Literature |
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| Severe microcephaly v9.13 | VPS36 | Ida Ertmanska Classified gene: VPS36 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.13 | VPS36 | Ida Ertmanska Added comment: Comment on list classification: While there are 3 unrelated pedigrees reported in literature with biallelic VPS36 variants and microcephaly, the severity of microcephaly is not stated. Hence, it is unclear whether this association fits into the scope of the Severe microcephaly panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.13 | VPS36 | Ida Ertmanska Gene: vps36 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.61 | VPS36 |
Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026). Sources: Literature |
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| Early onset or syndromic epilepsy v9.41 | VPS36 |
Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026). Sources: Literature |
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| Severe microcephaly v9.12 | VPS36 |
Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026). Sources: Literature |
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| Early onset or syndromic epilepsy v9.41 | VPS36 |
Ida Ertmanska gene: VPS36 was added gene: VPS36 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: VPS36 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS36 were set to 28600779; 42362802 Phenotypes for gene: VPS36 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: VPS36 was set to AMBER Added comment: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. Sources: Literature |
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| Intellectual disability v10.61 | VPS36 |
Ida Ertmanska gene: VPS36 was added gene: VPS36 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: VPS36 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS36 were set to 28600779; 42362802 Phenotypes for gene: VPS36 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: VPS36 was set to AMBER Added comment: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. Sources: Literature |
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| Severe microcephaly v9.12 | VPS36 |
Ida Ertmanska gene: VPS36 was added gene: VPS36 was added to Severe microcephaly. Sources: Literature Mode of inheritance for gene: VPS36 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS36 were set to 28600779; 42362802 Phenotypes for gene: VPS36 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: VPS36 was set to AMBER Added comment: PMID: 42362802 Chaurasia et al., 2026 Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs) Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype. Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5). PMID: 28600779 Monies et al., 2017 Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability. Sources: Literature |
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| Hereditary neuropathy or pain disorder v8.17 | POLR3A | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Alexander Rossor, there are 8 unrelated families reported with monoallelic variants and early-onset peripheral neuropathy. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.17 | POLR3A | Achchuthan Shanmugasundram Mode of inheritance for gene: POLR3A was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.16 | POLR3A |
Achchuthan Shanmugasundram Tag Q3_26_promote_green was removed from gene: POLR3A. Tag Q3_26_NHS_review tag was added to gene: POLR3A. Tag Q3_26_MOI tag was added to gene: POLR3A. |
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| Hereditary neuropathy or pain disorder v8.16 | POLR3A | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: POLR3A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.16 | POLR3A | Achchuthan Shanmugasundram Phenotypes for gene: POLR3A were changed from Bilateral hyperintensities on MRI from the superior cerebellar peduncle to the dentate nucleus / midbrain; Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, 607694; Adolescent onset progressive spastic ataxia, tremor, involvement of central sensory tracts, dental complications to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694; leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897; peripheral neuropathy, MONDO:0005244 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.15 | POLR3A | Achchuthan Shanmugasundram Publications for gene: POLR3A were set to 28459997 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.14 | DHTKD1 | Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: DHTKD1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.14 | DHTKD1 | Ida Ertmanska Phenotypes for gene: DHTKD1 were changed from ?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025 to ?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025; Charcot-Marie-Tooth disease axonal type 2Q, MONDO:0014012 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.13 | DHTKD1 | Ida Ertmanska Publications for gene: DHTKD1 were set to 23141294; 28902413; 29661920; 34571524 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.12 | POLR3A |
Achchuthan Shanmugasundram edited their review of gene: POLR3A: Added comment: PMID:42260910 (2026) reported 11 patients from 8 unrelated families identified with heterozygous missense variants in POLR3A. The patients presented with an early-onset, progressive sensorimotor peripheral polyneuropathy with intermediate to demyelinating ranges of nerve conduction slowing, occasionally accompanied with neurological or non-neurological features. White matter abnormalities that are characteristic for the biallelic Pol III-related disorders were not observed in the brain magnetic resonance imaging. Although biallelic variants in this gene has already been associated with phenotypes relevant for this panel on OMIM (MIM #607694, last accessed 26 July 2026) and ClinGen (with 'definitive; rating by Leukodystrophy and Leukoencephalopathy GCEP), monoallelic variants are not yet associated with relevant phenotypes in these resources.; Changed publications to: 42260910; Changed phenotypes to: Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694, leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897, peripheral neuropathy, MONDO:0005244; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Hereditary neuropathy or pain disorder v8.12 | DHTKD1 | Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: DHTKD1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.12 | DHTKD1 | Ida Ertmanska commented on gene: DHTKD1: Comment on list classification: While there are several patients reported with CMT and DHTKD1 variants (including the recurrent p.Tyr485Ter variant), the variants are of uncertain significance, and evidence for the association is limited. A knock in Dhtkd1 Y486* mouse model showed some signs of neuropathy on histology, but the motor performance was normal in the mutant mice. As reviewed by James Polke, high frequency of LOF variants in gnomAD and lack of a phenotype in carriers of AAKAD can be seen as refuting evidence. Hence, this gene should be downgraded from Green to Amber at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.12 | DHTKD1 | Ida Ertmanska edited their review of gene: DHTKD1: Changed publications to: 32169121, 35052424, 37880984, 41169655 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.12 | DHTKD1 |
Ida Ertmanska changed review comment from: PMID: 41169655 Başdemirci et al., 2025 Cohort of 58 patients with suspected CMT. Method: MLPA + NGS. Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1. PMID: 37880984 Menon et al., 2024 Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter. PMID: 35052424 Osmanovic et al., 2021 Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants. Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail: https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13. Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter). https://doi.org/10.4103/nsn.nsn_91_25 Beton et al. 2026 - case report of a 36-year-old male with a longstanding history of gait disturbances, presented with bilateral scapular winging, proximal upper limb weakness, pes cavus, and steppage gait. Genetic testing identified a heterozygous pathogenic variant in the DHTKD1 gene, consistent with CMT2Q (variant not specified).; to: PMID: 41169655 Başdemirci et al., 2025 Cohort of 58 patients with suspected CMT. Method: MLPA + NGS. Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1. PMID: 37880984 Menon et al., 2024 Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter. PMID: 35052424 Osmanovic et al., 2021 Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants. PMID: 32169121 Luan et al. 2020 - Knock-in mouse model Dhtkd1 Y486* - partially recapitulated the clinical phenotypes of CMT2Q patients. Dhtkd1 expression level in sciatic nerve of knock-in mice was significantly lower than in wild-type mice; histopathological phenotype was reminiscent of a peripheral neuropathy (reduced large axon diameter and abnormal myelination in peripheral nerves); mice displayed clear sensory defects, while no abnormalities in the motor performance were observed; also observed accumulation of mitochondria and an elevated energy metabolic state. Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail: https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13. Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter). https://doi.org/10.4103/nsn.nsn_91_25 Beton et al. 2026 - case report of a 36-year-old male with a longstanding history of gait disturbances, presented with bilateral scapular winging, proximal upper limb weakness, pes cavus, and steppage gait. Genetic testing identified a heterozygous pathogenic variant in the DHTKD1 gene, consistent with CMT2Q (variant not specified). |
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| Hereditary neuropathy or pain disorder v8.12 | DHTKD1 |
Ida Ertmanska changed review comment from: PMID: 41169655 Başdemirci et al., 2025 Cohort of 58 patients with suspected CMT. Method: MLPA + NGS. Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1. PMID: 37880984 Menon et al., 2024 Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter. PMID: 35052424 Osmanovic et al., 2021 Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants. Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail: https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13. Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter).; to: PMID: 41169655 Başdemirci et al., 2025 Cohort of 58 patients with suspected CMT. Method: MLPA + NGS. Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1. PMID: 37880984 Menon et al., 2024 Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter. PMID: 35052424 Osmanovic et al., 2021 Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants. Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail: https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13. Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter). https://doi.org/10.4103/nsn.nsn_91_25 Beton et al. 2026 - case report of a 36-year-old male with a longstanding history of gait disturbances, presented with bilateral scapular winging, proximal upper limb weakness, pes cavus, and steppage gait. Genetic testing identified a heterozygous pathogenic variant in the DHTKD1 gene, consistent with CMT2Q (variant not specified). |
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| Hereditary neuropathy or pain disorder v8.12 | DHTKD1 |
Ida Ertmanska changed review comment from: PMID: 41169655 Başdemirci et al., 2025 Cohort of 58 patients with suspected CMT. Method: MLPA + NGS. Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1. PMID: 37880984 Menon et al., 2024 Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter. PMID: 35052424 Osmanovic et al., 2021 Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.; to: PMID: 41169655 Başdemirci et al., 2025 Cohort of 58 patients with suspected CMT. Method: MLPA + NGS. Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1. PMID: 37880984 Menon et al., 2024 Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter. PMID: 35052424 Osmanovic et al., 2021 Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants. Case reports where heterozygous DHTKD1 variants are reported as causal, but not specified in detail: https://doi.org/10.1212/WNL.94.15_supplement.186 (Neurology), Kumar 2020 - Case report of a 15yo Indian male with CMT2 diagnosis (NCS and EMG consistent with CMT). He harboured a DHTKD1 variant in exon 13. Lee C and Jerath NU. Case Study of a Rare Pathogenic DHTKD1 Mutation Associated with CMT2Q. ICARE. 2024;3(3):22-24. - 68yo female with CMT2Q. Abnormal gait and clumsiness reported since her 50s. DHTKD1 variant not exactly specified but implied to be the same as in PMID:23141294 (p.Tyr485Ter). |
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| Hereditary neuropathy or pain disorder v8.12 | DHTKD1 |
Ida Ertmanska changed review comment from: PMID: 41169655 Başdemirci et al., 2025 Cohort of 58 patients with suspected CMT. Method: MLPA + NGS. Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1. PMID: 37880984 Menon et al., 2024 Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: c.1445T>C, p.Tyr485Ter. PMID: 35052424 Osmanovic et al., 2021 Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants.; to: PMID: 41169655 Başdemirci et al., 2025 Cohort of 58 patients with suspected CMT. Method: MLPA + NGS. Patient 12 = female, positive family history (but segregation study could not be performed), consanguinity noted; DHTKD1 c.1604G>T (G535V) variant detected - labelled VUS (PP3, PM2, BP1). 51 hets reported in gnomAD v4.1.1. PMID: 37880984 Menon et al., 2024 Report of a 72yo man who presented with a 2 years progressive history of respiratory and neck muscle weakness without significant bulbar and limb involvement - described as ALS-like. Clinical and electrophysiological examination revealed lower motor neuron involvement with widespread chronic denervation and reinnervation. Clinical WES revealed a heterozygous variant in exon 8 of DHTKD1: p.Tyr485Ter. PMID: 35052424 Osmanovic et al., 2021 Two independent European ALS cohorts (n = 643 cases). 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants. |
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| Hereditary neuropathy or pain disorder v8.12 | DHTKD1 | Ida Ertmanska reviewed gene: DHTKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35052424, 37880984, 41169655; Phenotypes: ?Charcot-Marie-Tooth disease, axonal, type 2Q, OMIM:615025, Charcot-Marie-Tooth disease axonal type 2Q, MONDO:0014012; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.12 | MT-TV | Achchuthan Shanmugasundram Classified gene: MT-TV as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.12 | MT-TV |
Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor and Christopher Record, there is sufficient scientific evidence available for the association of MT-TV variants with hereditary neuropathy. However, it should be noted that the GMS reviewers previously disagreed on the inclusion of genes of the mitochondrial genome including MT-TV with green rating on other WGS/ non-WGS panels suggesting that an alternative test is more suitable for syndromic mitochondrial disease: R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing. Hence, this gene has been tagged for expert review from GLH experts. |
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| Hereditary neuropathy or pain disorder v8.12 | MT-TV | Achchuthan Shanmugasundram Gene: mt-tv has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.11 | MT-TV | Achchuthan Shanmugasundram Phenotypes for gene: MT-TV were changed from peripheral neuropathy; spasticity to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.10 | MT-TV | Achchuthan Shanmugasundram Publications for gene: MT-TV were set to 32715519: 39468830: 38371303 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.9 | MT-TV | Achchuthan Shanmugasundram Tag locus-type-rna-transfer tag was added to gene: MT-TV. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v8.9 | MT-TV |
Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: MT-TV. Tag Q3_26_promote_green tag was added to gene: MT-TV. |
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| Hereditary neuropathy or pain disorder v8.9 | MT-TV | Achchuthan Shanmugasundram reviewed gene: MT-TV: Rating: GREEN; Mode of pathogenicity: None; Publications: 32715519, 38371303, 39468830, 39243325; Phenotypes: mitochondrial disease, MONDO:0044970, Charcot-Marie-Tooth disease, MONDO:0015626; Mode of inheritance: MITOCHONDRIAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.4 | FAM210A | Achchuthan Shanmugasundram Classified gene: FAM210A as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.4 | FAM210A | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with ectodermal dysplasia and biallelic FAM210A variants. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.4 | FAM210A | Achchuthan Shanmugasundram Gene: fam210a has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.3 | FAM210A | Achchuthan Shanmugasundram commented on gene: FAM210A: The 'new-gene-name' tag has been added as the official HGNC gene symbol is MIMS1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.3 | FAM210A | Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: FAM210A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FAM210A | Achchuthan Shanmugasundram Classified gene: FAM210A as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FAM210A | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with skeletal dysplasia and biallelic FAM210A variants. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.33 | FAM210A | Achchuthan Shanmugasundram Gene: fam210a has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.32 | FAM210A | Achchuthan Shanmugasundram commented on gene: FAM210A: The 'new-gene-name' tag has been added as the official HGNC gene symbol is MIMS1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.32 | FAM210A | Achchuthan Shanmugasundram Tag new-gene-name tag was added to gene: FAM210A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ectodermal dysplasia v5.3 | FAM210A |
Achchuthan Shanmugasundram gene: FAM210A was added gene: FAM210A was added to Ectodermal dysplasia. Sources: Literature Q3_26_promote_green tags were added to gene: FAM210A. Mode of inheritance for gene: FAM210A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM210A were set to 42410297 Phenotypes for gene: FAM210A were set to Spondyloepimetaphyseal dysplasia with tracheal stenosis and ectodermal dysplasia, OMIM:621650 Review for gene: FAM210A was set to GREEN Added comment: PMID:42410297 (2026) reported five patients from four unrelated families with skeletal dysplasia phenotype characterised by spondyloepimetaphyseal dysplasiachondrodysplasia with short stature (all patents), tracheal stenosis (all patients), conical teeth and/or early tooth decay, and sparse hair suggestive of ectodermal dysplasia (in three unrelated patients). They were identified with biallelic variants in FAM210A gene (new gene name - MIMS1) - homozygous missense variants in three families and compound heterozygous nonsense variants in the first family with two siblings. This gene has been associated with relevant phenotype in OMIM (MIM #621650, last accessed 24 July 2026), but not in Gene2Phenotype or ClinGen. Sources: Literature |
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| Skeletal dysplasia v9.32 | FAM210A |
Achchuthan Shanmugasundram gene: FAM210A was added gene: FAM210A was added to Skeletal dysplasia. Sources: Literature Q3_26_promote_green tags were added to gene: FAM210A. Mode of inheritance for gene: FAM210A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM210A were set to 42410297 Phenotypes for gene: FAM210A were set to Spondyloepimetaphyseal dysplasia with tracheal stenosis and ectodermal dysplasia, OMIM:621650 Review for gene: FAM210A was set to GREEN Added comment: PMID:42410297 (2026) reported five patients from four unrelated families with skeletal dysplasia phenotype characterised by spondyloepimetaphyseal dysplasiachondrodysplasia with short stature (all patents), tracheal stenosis (all patients), conical teeth and/or early tooth decay, and sparse hair suggestive of ectodermal dysplasia (in three unrelated patients). They were identified with biallelic variants in FAM210A gene (new gene name - MIMS1) - homozygous missense variants in three families and compound heterozygous nonsense variants in the first family with two siblings. This gene has been associated with relevant phenotype in OMIM (MIM #621650, last accessed 24 July 2026), but not in Gene2Phenotype or ClinGen. Sources: Literature |
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| Intellectual disability v10.60 | SNW1 | Achchuthan Shanmugasundram Classified gene: SNW1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.60 | SNW1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of this gene with intellectual disability (moderate-severe), it should be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.60 | SNW1 | Achchuthan Shanmugasundram Gene: snw1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.59 | SNW1 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SNW1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.59 | SNW1 |
Achchuthan Shanmugasundram changed review comment from: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature; to: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 July 2026), Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature |
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| Early onset or syndromic epilepsy v9.40 | SNW1 | Achchuthan Shanmugasundram Classified gene: SNW1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.40 | SNW1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of this gene with seizures, it should be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.40 | SNW1 | Achchuthan Shanmugasundram Gene: snw1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.39 | SNW1 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SNW1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.39 | SNW1 |
Achchuthan Shanmugasundram changed review comment from: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature; to: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 July 2026), Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature |
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| Severe microcephaly v9.11 | SNW1 | Achchuthan Shanmugasundram Classified gene: SNW1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.11 | SNW1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of this gene with severe microcephaly, it should be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.11 | SNW1 | Achchuthan Shanmugasundram Gene: snw1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v9.10 | SNW1 |
Achchuthan Shanmugasundram changed review comment from: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature; to: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 July 2026), Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature |
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| Severe microcephaly v9.10 | SNW1 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SNW1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.39 | SNW1 |
Achchuthan Shanmugasundram gene: SNW1 was added gene: SNW1 was added to Early onset or syndromic epilepsy. Sources: Literature Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SNW1 were set to 40608414 Phenotypes for gene: SNW1 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149 Review for gene: SNW1 was set to GREEN Added comment: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature |
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| Intellectual disability v10.59 | SNW1 |
Achchuthan Shanmugasundram gene: SNW1 was added gene: SNW1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SNW1 were set to 40608414 Phenotypes for gene: SNW1 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149 Review for gene: SNW1 was set to GREEN Added comment: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature |
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| Severe microcephaly v9.10 | SNW1 |
Achchuthan Shanmugasundram gene: SNW1 was added gene: SNW1 was added to Severe microcephaly. Sources: Literature Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SNW1 were set to 40608414 Phenotypes for gene: SNW1 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149 Review for gene: SNW1 was set to GREEN Added comment: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above. Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1). There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis. This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia. Sources: Literature |
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| Ataxia and cerebellar anomalies - childhood onset v9.12 | ATN1_CAG | Ida Ertmanska Phenotypes for STR: ATN1_CAG were changed from Dentatorubral-pallidoluysian atrophy, OMIM:125370 to Dentatorubral-pallidoluysian atrophy, OMIM:125370; dentatorubral-pallidoluysian atrophy, MONDO:0007435 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.11 | ATN1_CAG | Ida Ertmanska Publications for STR: ATN1_CAG were set to 20301664; 8136840; 20301664; 8136840; 8136826; 7614090 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.7 | ATN1_CAG |
Ida Ertmanska Tag Q3_26_NHS_review tag was added to STR: ATN1_CAG. Tag Q3_26_promote_green tag was added to STR: ATN1_CAG. |
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| Leukodystrophy, adult onset v7.7 | ATN1_CAG | Ida Ertmanska Phenotypes for STR: ATN1_CAG were changed from to Dentatorubral-pallidoluysian atrophy, OMIM:125370; dentatorubral-pallidoluysian atrophy, MONDO:0007435 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.6 | ATN1_CAG | Ida Ertmanska Publications for STR: ATN1_CAG were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.5 | ATN1_CAG | Ida Ertmanska Classified STR: ATN1_CAG as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.5 | ATN1_CAG | Ida Ertmanska Added comment: Comment on list classification: As reviewed by Luke Stuart, there are numerous individuals reported in literature with ATN1 CAG repeats and adult-onset Dentatorubral-Pallidoluysian Atrophy, which entails widespread white matter atrophy. Hence, this STR should be promoted to Green on Adult onset leukodystrophy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.5 | ATN1_CAG | Ida Ertmanska Str: atn1_cag has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.10 | ATN1_CAG | Ida Ertmanska reviewed STR: ATN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.10 | ATN1_CAG | Ida Ertmanska Tag Q3_26_promote_green tag was added to STR: ATN1_CAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.10 | ATN1_CAG | Ida Ertmanska Tag watchlist was removed from STR: ATN1_CAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - childhood onset v9.10 | ATN1_CAG | Luke Stuart reviewed STR: ATN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20589872, 22527233; Phenotypes: Dentatorubral-pallidoluysian atrophy, 125370; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.4 | ATN1_CAG | Luke Stuart reviewed STR: ATN1_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 8586978, 8370212, 1837247, 9409354, 40298952, 15210537, 8167052; Phenotypes: Dentatorubral-pallidoluysian atrophy, 125370; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.29 | LONP1 | Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373) to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.28 | LONP1 | Achchuthan Shanmugasundram Publications for gene: LONP1 were set to 25574826; 25808063 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.27 | LONP1 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.27 | LONP1 | Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.26 | LONP1 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: LONP1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.26 | LONP1 | Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.16 | LONP1 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.16 | LONP1 | Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.15 | LONP1 | Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373) to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.14 | LONP1 | Achchuthan Shanmugasundram Publications for gene: LONP1 were set to PMID: 25574826; PMID: 25808063 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.13 | LONP1 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: LONP1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.13 | LONP1 | Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.15 | LONP1 | Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.; to: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.15 | LONP1 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of both monoallelic and biallelic variants in LONP1 with disease. Hence, the MOI can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.15 | LONP1 | Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.14 | LONP1 | Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS syndrome, 600373 to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.13 | LONP1 | Achchuthan Shanmugasundram Publications for gene: LONP1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.12 | LONP1 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: LONP1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.12 | LONP1 | Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.58 | LONP1 | Achchuthan Shanmugasundram Phenotypes for gene: LONP1 were changed from CODAS syndrome, 600373; Cerebral, ocular, dental, auricular, and skeletal anomalies syndrome to CODAS syndrome, OMIM:600373; CODAS syndrome, MONDO:0010879; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.57 | LONP1 | Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least three unrelated individuals reported with monoallelic LONP1 variants and syndromic intellectual disability. Hence, the MOI for this gene can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.57 | LONP1 | Achchuthan Shanmugasundram Mode of inheritance for gene: LONP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.56 | LONP1 | Achchuthan Shanmugasundram edited their review of gene: LONP1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.56 | LONP1 | Achchuthan Shanmugasundram Publications for gene: LONP1 were set to 25574826; 20503327; 11471171; 1887855 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.55 | LONP1 | Achchuthan Shanmugasundram Tag Q3_26_MOI tag was added to gene: LONP1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.55 | LONP1 | Achchuthan Shanmugasundram reviewed gene: LONP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40931319; Phenotypes: CODAS syndrome, OMIM:600373, CODAS syndrome, MONDO:0010879, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.55 | CDK20 | Achchuthan Shanmugasundram Tag Q3_26_promote_green was removed from gene: CDK20. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.55 | CDK20 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are two unrelated live individuals reported with biallelic CDK20 variants and with a multisystem phenotype including global developmental delay and/or intellectual disability. Hence, this gene should be rated amber with the current evidence. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.55 | CDK20 |
Achchuthan Shanmugasundram changed review comment from: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Ventriculomegaly and/ or hydrocephalus was reported in four foetuses from two unrelated families and a live child from another family. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature; to: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature |
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| Intellectual disability v10.55 | CDK20 | Achchuthan Shanmugasundram edited their review of gene: CDK20: Changed rating: AMBER; Changed phenotypes to: ciliopathy, MONDO:0005308, Ventriculomegaly, HP:0002119, hydrocephalus, MONDO:0001150, Global developmental delay, HP:0001263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.55 | CDK20 | Achchuthan Shanmugasundram Entity copied from Hydrocephalus v5.14 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.55 | CDK20 |
Achchuthan Shanmugasundram gene: CDK20 was added gene: CDK20 was added to Intellectual disability. Sources: Expert Review Amber,Literature Q3_26_promote_green tags were added to gene: CDK20. Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK20 were set to 42409022 Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150 |
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| Holoprosencephaly v6.3 | CDK20 |
Achchuthan Shanmugasundram gene: CDK20 was added gene: CDK20 was added to Holoprosencephaly. Sources: Literature Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK20 were set to 42409022 Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150; holoprosencephaly, MONDO:0016296 Review for gene: CDK20 was set to RED Added comment: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Semilobar holoprosencephaly was identified by ultrasound in one foetus (family III). These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature |
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| Clefting v7.8 | CDK20 |
Achchuthan Shanmugasundram changed review comment from: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Midline cleft lip/ palate was reported in five individuals from four families, of which three are foetuses. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature; to: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Midline cleft lip/ palate was reported in five individuals from four families, of which four are foetuses. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature |
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| Clefting v7.8 | CDK20 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are Fien individuals from four unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including midline cleft lip/ palate. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.8 | CDK20 |
Achchuthan Shanmugasundram changed review comment from: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Ventriculomegaly and/ or hydrocephalus was reported in four foetuses from two unrelated families and a live child from another family. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature; to: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Midline cleft lip/ palate was reported in five individuals from four families, of which three are foetuses. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature |
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| Clefting v7.8 | CDK20 | Achchuthan Shanmugasundram Entity copied from Hydrocephalus v5.14 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v7.8 | CDK20 |
Achchuthan Shanmugasundram gene: CDK20 was added gene: CDK20 was added to Clefting. Sources: Expert Review Amber,Literature Q3_26_promote_green tags were added to gene: CDK20. Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK20 were set to 42409022 Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150 |
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| Hydrocephalus v5.14 | CDK20 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green raring in the next GMS update.; to: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.14 | CDK20 | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are five unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype, which included five foetuses from three families (resulting in termination of pregnancies) and two live children. This gene can therefore promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype including ventriculomegaly/ hydrocephalus. Hence, this gene can be promoted to green raring in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.14 | CDK20 |
Achchuthan Shanmugasundram changed review comment from: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature; to: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. Ventriculomegaly and/ or hydrocephalus was reported in four foetuses from two unrelated families and a live child from another family. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature |
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| Hydrocephalus v5.14 | CDK20 | Achchuthan Shanmugasundram Entity copied from Fetal anomalies v7.32 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.14 | CDK20 |
Achchuthan Shanmugasundram gene: CDK20 was added gene: CDK20 was added to Hydrocephalus. Sources: Expert Review Amber,Literature Q3_26_promote_green tags were added to gene: CDK20. Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK20 were set to 42409022 Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150 |
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| Fetal anomalies v7.32 | CDK20 | Achchuthan Shanmugasundram Classified gene: CDK20 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v7.32 | CDK20 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with biallelic CDK20 variants and with a multisystem phenotype, which included five foetuses from three families (resulting in termination of pregnancies) and two live children. This gene can therefore promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v7.32 | CDK20 | Achchuthan Shanmugasundram Gene: cdk20 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v7.31 | CDK20 | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: CDK20. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v7.31 | CDK20 |
Achchuthan Shanmugasundram gene: CDK20 was added gene: CDK20 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: CDK20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK20 were set to 42409022 Phenotypes for gene: CDK20 were set to ciliopathy, MONDO:0005308; Ventriculomegaly, HP:0002119; hydrocephalus, MONDO:0001150 Review for gene: CDK20 was set to GREEN Added comment: PMID:42409022 (2026) reported a cohort of seven individuals from five unrelated families including five deceased foetuses and two living children presenting with a consistent pattern of multisystem anomalies. Recurrent prenatal findings included severe ventriculomegaly or holoprosencephaly, midline cleft lip and palate, cryptophthalmos and/or anophthalmia, and limb anomalies, resulting in a decision to terminate the pregnancy. Postmortem examinations demonstrated a spectrum of brain malformations, including aqueduct stenosis, agenesis of the olfactory bulb and tract, absent pituitary stalk, corticospinal tract abnormalities, corpus callosum abnormalities, absent septum pellucidum, polydactyly and a sandal toe gap. The two living individuals showed overlapping features, including structural brain anomalies, panhypopituitarism, genital anomalies, and severe global developmental delay. These families were identified with either homozygous or compound heterozygous variants in CDK20 gene, with six variants in total. Immunoblot analysis of fibroblasts derived from two affected fetuses with the homozygous c.687+6T>C variant demonstrated reduced CDK20 levels, and were significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. This gene has not yet been associated with any relevant phenotypes either in OMIM (last accessed 23 July 2026) or in Gene2Phenotype. Sources: Literature |
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| Monogenic hearing loss v6.33 | COL4A6 | Ida Ertmanska Mode of inheritance for gene: COL4A6 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.32 | COL4A6 | Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with deafness.; to: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with COL4A6-related deafness. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.32 | COL4A6 | Ida Ertmanska commented on gene: COL4A6: Comment on list classification: There are more than 3 unrelated male individuals reported in literature with hemizygous COL4A6 variants and non-syndromic hearing loss. Hence, this gene can be promoted to Green at the next update. MOI should be set to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as little segregation evidence is provided for the families - unclear if female carriers may also present with deafness. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.32 | COL4A6 | Ida Ertmanska edited their review of gene: COL4A6: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.32 | COL4A6 |
Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP).; to: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). Parents unaffected, not genotyped. PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous affected mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP). |
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| Monogenic hearing loss v6.32 | COL4A6 | Ida Ertmanska Phenotypes for gene: COL4A6 were changed from Deafness, X-linked 6, OMIM:300914 to ?Deafness, X-linked 6 , OMIM:300914; hearing loss, X-linked 6, MONDO:0010484 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.31 | COL4A6 | Ida Ertmanska Publications for gene: COL4A6 were set to PMID: 23714752; 7592929; 7711741; 7972123; 8125972; 8175748; 8356449; 8661006; 9463311 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.30 | COL4A6 | Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: COL4A6. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.30 | COL4A6 |
Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).; to: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). The association between COL4A6 and hearing loss, X-linked 6 was classified as Limited in ClinGen (Feb 2022, Hearing Loss GCEP). |
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| Monogenic hearing loss v6.30 | COL4A6 |
Ida Ertmanska changed review comment from: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951 + 1 G > T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 varinats in the two kindreds, which are also likely to contribute to hearing loss. The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026).; to: PMID: 41092388 Owrang et al., 2026 Study identified two families affected by multiple genetic disorders. The first family presented a missense COL4A6 variant (NM_033641.4: c.1480G>A p.(Gly494Arg)), accounting for hearing loss, while a likely pathogenic HEXA variant (NM_000520.6: c.902T>G p.(Met301Arg)) explained Tay-Sachs disease features. The second family exhibited a synonymous COL4A6 variant (NM_033641.4: c.1767G>A p.(Pro589=)), leading to partial exon skipping and hearing loss, along with a pathogenic splice-site variant in DYM (NM_001353214.3: c.1125 + 1G>T p.?), causing the Dyggve-Melchior-Clausen disease. PMID: 40928595 Jagannath et al., 2025 Family 4, Indian origin - male proband with sensorineural hearing loss and a hemizygous variant in COL4A6: c.227G > A (p.Gly76Glu). PMID: 39272213 Feng et al., 2024 Individual 23 - male, Chinese, with congenital hearing loss (Profound, SNHL, Malformed cochlea; CI) - harboured a hemizygous COL4A6 variant c.1456G>A, p.G486S. PMID: 33840813 O'Brien et al., 2022 Report of 2 unrelated families with male probands hemizygous for COL4A6 variants: NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951+1G>C. An in vitro minigene splicing assay revealed that c.951+1G>T leads to skipping of exon 15. Both variants were inherited from heterozygous mothers. However, the molecular diagnosis is complicated by presence of GJB2 and GJB6 variants in the two kindreds, which are also likely to contribute to hearing loss. Functional evidence: PMID: 33848312 Tang et al., 2021 - loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation - LOF variants unlikely to cause hearing loss The gene is linked to ?Deafness, X-linked 6, OMIM:300914 (OMIM accessed 22nd July 2026). |
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| Intellectual disability v10.54 | NSF | Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: This gene is now associated with a relevant phenotype in OMIM (MIM #619340), but not in Gene2Phenotype.; to: Comment on phenotypes: This gene is now associated with a relevant phenotype in OMIM (MIM #619340, last accessed 22 July 2026), but not in Gene2Phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.54 | NSF | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.54 | NSF | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.54 | NSF | Achchuthan Shanmugasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.38 | NSF | Achchuthan Shanmugasundram Classified gene: NSF as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.38 | NSF | Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with monoallelic variants in NSF gene and with infantile-onset epileptic encephalopathy. Hence, this gene can be promote to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.38 | NSF | Achchuthan Shanmugasundram Gene: nsf has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.30 | COL4A6 | Ida Ertmanska reviewed gene: COL4A6: Rating: GREEN; Mode of pathogenicity: None; Publications: 33840813, 39272213, 40928595, 41092388; Phenotypes: ?Deafness, X-linked 6 , OMIM:300914, hearing loss, X-linked 6, MONDO:0010484; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.37 | NSF | Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: NSF. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.37 | NSF | Achchuthan Shanmugasundram Publications for gene: NSF were set to 31675180; 36645181 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.36 | NSF | Achchuthan Shanmugasundram Phenotypes for gene: NSF were changed from Developmental and epileptic encephalopathy 96, OMIM:619340 to Developmental and epileptic encephalopathy 96, OMIM:619340; developmental and epileptic encephalopathy 96, MONDO:0023659 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.35 | NSF | Achchuthan Shanmugasundram Mode of inheritance for gene: NSF was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.34 | NSF |
Achchuthan Shanmugasundram changed review comment from: PMID:36645181 describes the two previously reported cases from PMID:31675180. The third case reported had a very mild phenotype and did not present with epilepsy and had normal development. Hence, this gene should remain AMBER. This gene has now been associated with relevant phenotype in OMIM (MIM #619340), but not in Gene2Phenotype.; to: PMID:36645181 (2023) described the two previously reported cases from PMID:31675180 (2019) with de novo pathogenic variants in NSF gene and with early infantile epileptic encephalopathy. The third case reported with a de novo missense variant in NSF gene had a very mild phenotype and did not present with epilepsy and had normal development. PMID:42045022 (2026) reported a cohort of 38 previously unsolved infantile-onset developmental epileptic encephalopathy (DEE) probands that were sequenced with long-read genome sequencing, of which one proband was identified with a heterozygous c.664G>A (p.Gly222Ser) variant in NSF gene. This patient was not previously identified with a variant in this gene through exome sequencing because the NSF gene is known to be in a multiple alignment region. This gene has been associated with relevant phenotype in OMIM (MIM #619340, last accessed 22 July 2026), but not in Gene2Phenotype. |
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| Early onset or syndromic epilepsy v9.34 | NSF | Achchuthan Shanmugasundram edited their review of gene: NSF: Changed rating: GREEN; Changed publications to: 31675180, 36645181, 42045022; Changed phenotypes to: Developmental and epileptic encephalopathy 96, OMIM:619340, developmental and epileptic encephalopathy 96, MONDO:0023659 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.7 | ZFHX4 |
Ida Ertmanska Tag Q3_26_expert_review was removed from gene: ZFHX4. Tag Q3_26_NHS_review tag was added to gene: ZFHX4. |
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| Congenital hyperinsulinism v3.9 | CACNA1C |
Ida Ertmanska Tag Q3_26_NHS_review tag was added to gene: CACNA1C. Tag Q3_26_demote_red tag was added to gene: CACNA1C. |
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| Congenital hyperinsulinism v3.9 | CACNA1C | Ida Ertmanska reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: 30067485, 35897673, 39420001; Phenotypes: Timothy syndrome, OMIM:601005; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.7 | ZFHX4 |
Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: ZFHX4. Tag Q3_26_promote_green tag was added to gene: ZFHX4. |
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| Congenital fibrosis of the extraocular muscles v2.7 | ZFHX4 | Ida Ertmanska Phenotypes for gene: ZFHX4 were changed from Isolated congenital ptosis to congenital ptosis, MONDO:0008340 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.6 | ZFHX4 | Ida Ertmanska Publications for gene: ZFHX4 were set to PMID: 41524020; 11935336; 32962661 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.5 | ZFHX4 | Ida Ertmanska Classified gene: ZFHX4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.5 | ZFHX4 | Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated patients reported in literature with heterozygous ZFHX4 variants and isolated congenital ptosis. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.5 | ZFHX4 | Ida Ertmanska Gene: zfhx4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.4 | ZFHX4 | Ida Ertmanska edited their review of gene: ZFHX4: Changed publications to: 41524020, 32962661, 17987257, 11935336 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital fibrosis of the extraocular muscles v2.4 | ZFHX4 |
Ida Ertmanska changed review comment from: PMID: 41524020 Zhang et al., 2026 Cohort of patients with isolated congenital ptosis. Seq method: WES. Three novel heterozygous variants in ZFHX4, c.5145C>A (p.N1715K), c.10382C>T (p.A3461V), and c.10795G>A (p.A3599T), were identified in three patients of Han Chinese origin. PMID: 32962661 Adhikari et al., 2020 Report of a Nepalese proband with congenital ptosis and a c.12411G>T, p.Leu4137Phe variant in exon 12 of ZFHX4. Same variant reported in a Japanese kindred with hereditary congenital blepharoptosis (PMID: 17987257, Nakashima et al., 2008). This gene is not yet associated with a disease entity in OMIM. ZFHX4 association with AD syndromic complex neurodevelopmental disorder was classified as Strong in ClinGen in December 2025 (Intellectual Disability and Autism GCEP).; to: PMID: 41524020 Zhang et al., 2026 Cohort of patients with isolated congenital ptosis. Seq method: WES. Three novel heterozygous variants in ZFHX4, c.5145C>A (p.N1715K), c.10382C>T (p.A3461V), and c.10795G>A (p.A3599T), were identified in three patients of Han Chinese origin. PMID: 32962661 Adhikari et al., 2020 Report of a Nepalese proband with congenital ptosis and a c.12411G>T, p.Leu4137Phe variant in exon 12 of ZFHX4. Same variant reported in a Japanese kindred with hereditary congenital blepharoptosis (PMID: 17987257, Nakashima et al., 2008). PMID: 11935336 McMullan et al., 2002 Report of a patient with congenital bilateral isolated ptosis and a de novo balanced translocation 46,XY,t(1;8)(p34.3;q21.12). The 1p breakpoint does not disrupt a coding sequence, whereas the chromosome 8 breakpoint disrupts the ZFHX4 gene. This gene is not yet associated with a disease entity in OMIM. ZFHX4 association with AD syndromic complex neurodevelopmental disorder was classified as Strong in ClinGen in December 2025 (Intellectual Disability and Autism GCEP). |
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| Congenital fibrosis of the extraocular muscles v2.4 | ZFHX4 | Ida Ertmanska reviewed gene: ZFHX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 41524020, 32962661, 17987257; Phenotypes: congenital ptosis, MONDO:0008340; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.12 | TIMM8A | Ida Ertmanska Phenotypes for gene: TIMM8A were changed from Mohr-Tranebjaerg syndrome, 304700 to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.11 | TIMM8A | Ida Ertmanska Publications for gene: TIMM8A were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.10 | TIMM8A | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.10 | TIMM8A | Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Possible mitochondrial disorder, nuclear genes v5.10 | TIMM8A | Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11601506, 22736418, 40597358; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.30 | TIMM8A | Ida Ertmanska Phenotypes for gene: TIMM8A were changed from #304700:Mohr-Tranebjaerg syndrome; hearing loss; Deafness, X-linked 1, progressive to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.29 | TIMM8A | Ida Ertmanska Publications for gene: TIMM8A were set to PMID: 10051608; 10878669; 11405816; 11601506; 11875042; 11956200; 15037720; 15254020; 15710860; 16411215; 8380905; 8841189 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.28 | TIMM8A | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.28 | TIMM8A | Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females (1 presenting with deafness) reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monogenic hearing loss v6.28 | TIMM8A | Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11601506, 22736418, 40597358; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.13 | TIMM8A | Ida Ertmanska Phenotypes for gene: TIMM8A were changed from Disorders of the mitochondrial import system; Deafness, X-linked 1, progressive; Mohr-Tranebjaerg syndrome, 304700; Jensen syndrome, 311150 to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.12 | TIMM8A | Ida Ertmanska Publications for gene: TIMM8A were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.11 | TIMM8A | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.11 | TIMM8A | Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mitochondrial disorders v10.11 | TIMM8A | Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11601506, 22736418, 40597358; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.26 | TIMM8A | Ida Ertmanska Phenotypes for gene: TIMM8A were changed from Mohr-Tranebjaerg syndrome, 304700; Jensen syndrome, 311150; Disorders of the mitochondrial import system; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Deafness, X-linked 1, progressive to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.25 | TIMM8A | Ida Ertmanska Publications for gene: TIMM8A were set to 27604308 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.24 | TIMM8A | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.24 | TIMM8A | Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.24 | TIMM8A | Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 11601506, 22736418, 40597358; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.6 | TIMM8A | Ida Ertmanska commented on gene: TIMM8A: Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.6 | TIMM8A | Ida Ertmanska Phenotypes for gene: TIMM8A were changed from Mohr-Tranebjaerg syndrome, OMIM:304700 to Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.5 | TIMM8A | Ida Ertmanska Publications for gene: TIMM8A were set to 22736418; 32820032 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.4 | TIMM8A | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: TIMM8A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.4 | TIMM8A | Ida Ertmanska edited their review of gene: TIMM8A: Changed publications to: 11601506, 22736418, 40597358 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.4 | TIMM8A |
Ida Ertmanska changed review comment from: PMID: 40597358 Ventura et al., 2025 Report of a 16yo male with 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI; no hearing loss. WES detected a hemizygous TIMM8A variant c.98_101dupAGCA. The variant was inherited from a heterozygous mother, 43yo, who had recurrent muscle spasms - confirmed generalized dystonia, particularly affecting the upper extremities and cervical muscles. Maternal uncle showed motor clumsiness and finger spasms in childhood. Neither had hearing loss or visual impairment. PMID: 22736418 Ha et al., 2012 Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. Cognitive decline was noted in her 50s.; to: PMID: 40597358 Ventura et al., 2025 Report of a 16yo male with 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI; no hearing loss. WES detected a hemizygous TIMM8A variant c.98_101dupAGCA. The variant was inherited from a heterozygous mother, 43yo, who had recurrent muscle spasms - confirmed generalized dystonia, particularly affecting the upper extremities and cervical muscles. Maternal uncle showed motor clumsiness and finger spasms in childhood. Neither had hearing loss or visual impairment. PMID: 22736418 Ha et al., 2012 Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. Cognitive decline was noted in her 50s. PMID: 11601506 Swerdlow & Wooten, 2001 Kindred with Mohr-Tranebjaerg syndrome. Proband is a 30yo male with congenital deafness, and generalised dystonia starting around 28yo. Proband's mother reported head shaking, chronic neck muscle pain, and writer's cramp since age 25yrs. 1 female sibling of the proband was unaffected, while the other reported head shaking and writer's cramp with onset in late teens / early 20s. Affected patients harboured TIMM8A (old name DDP1) c.108del. |
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| Dystonia, chorea or related movement disorder, adult onset v6.4 | TIMM8A | Ida Ertmanska edited their review of gene: TIMM8A: Changed phenotypes to: Mohr-Tranebjaerg syndrome, OMIM:304700, deafness dystonia syndrome, MONDO:0010578 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.4 | TIMM8A | Ida Ertmanska edited their review of gene: TIMM8A: Changed publications to: 22736418, 40597358 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.4 | TIMM8A |
Ida Ertmanska changed review comment from: PMID: 22736418 Ha et al., 2012 Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs.; to: PMID: 40597358 Ventura et al., 2025 Report of a 16yo male with 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI; no hearing loss. WES detected a hemizygous TIMM8A variant c.98_101dupAGCA. The variant was inherited from a heterozygous mother, 43yo, who had recurrent muscle spasms - confirmed generalized dystonia, particularly affecting the upper extremities and cervical muscles. Maternal uncle showed motor clumsiness and finger spasms in childhood. Neither had hearing loss or visual impairment. PMID: 22736418 Ha et al., 2012 Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. Cognitive decline was noted in her 50s. |
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| Leukodystrophy, adult onset v7.4 | ATN1_CAG |
Eleanor Williams ATN1 was changed to ATN1_CAG Source NHS GMS was removed from STR: ATN1_CAG. Source Literature was added to STR: ATN1_CAG. Tag STR was added to STR: ATN1_CAG. |
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| Dystonia, chorea or related movement disorder, adult onset v6.4 | TIMM8A |
Ida Ertmanska changed review comment from: PMID: 22736418 Ha et al., 2012 Report of a female proband (kindred B) hemizygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs.; to: PMID: 22736418 Ha et al., 2012 Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. |
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| Dystonia, chorea or related movement disorder, adult onset v6.4 | TIMM8A | Ida Ertmanska reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 22736418; Phenotypes: Mohr-Tranebjaerg syndrome, OMIM:304700; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v7.30 | TMEM251 | Eleanor Williams Publications for gene: TMEM251 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fetal anomalies v7.29 | TMEM251 | Eleanor Williams Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex, Ain-Naz type, OMIM:619345 to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.3 | ATN1 | Lucy Jackson edited their review of STR: ATN1: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leukodystrophy, adult onset v7.3 | ATN1 |
Lucy Jackson STR: ATN1 was added STR: ATN1 was added to Adult onset leukodystrophy. Sources: NHS GMS Mode of inheritance for STR: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted STR: ATN1 was marked as current diagnostic Added comment: National Inherited White Matter Disorders MDT requests that this STR is added to the R62 panel Sources: NHS GMS |
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| Hereditary neuropathy or pain disorder v8.9 | OGDH |
Alexander Rossor gene: OGDH was added gene: OGDH was added to Hereditary neuropathy or pain disorder. Sources: Expert list Mode of inheritance for gene: OGDH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: OGDH were set to 42266417 Phenotypes for gene: OGDH were set to peripheral neuropathy; cerebellar ataxia; optic neuropathy Mode of pathogenicity for gene: OGDH was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: OGDH was set to AMBER Added comment: Only two families described so far Sources: Expert list |
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| Hereditary neuropathy or pain disorder v8.9 | POLR3A | Alexander Rossor edited their review of gene: POLR3A: Added comment: 8 unrelated patients. Should also add monoalleleic POLR3A variants to the panel (not just bialleleic); Changed publications to: 42260910; Changed phenotypes to: Early onset peripheral neuropathy; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | TMEM251 | Ida Ertmanska changed review comment from: Comment on list classification: There are now three unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now three unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | TMEM251 | Ida Ertmanska changed review comment from: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET.; to: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | TMEM251 | Ida Ertmanska changed review comment from: Comment on list classification: There are now four unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now three unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | TMEM251 | Ida Ertmanska Classified gene: TMEM251 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | TMEM251 | Ida Ertmanska Added comment: Comment on list classification: There are now four unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, and joint contractures. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.15 | TMEM251 | Ida Ertmanska Gene: tmem251 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.14 | TMEM251 |
Ida Ertmanska changed review comment from: PMID: 41858182 Sperb-Ludwig et al., 2026 Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more). PMID: 40171858 Kariminejad et al., 2025 Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD. PMID:33252156 Ain et al., 2021 Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities. Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family). Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes). Sources: Literature; to: PMID: 41858182 Sperb-Ludwig et al., 2026 Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more). PMID: 40171858 Kariminejad et al., 2025 Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD. PMID:33252156 Ain et al., 2021 Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities. 2 individuals from family NMD02 were noted to have severe joint contractures, which led to losing their ability to walk. Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family). Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes). Sources: Literature |
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| Arthrogryposis v10.14 | TMEM251 | Ida Ertmanska Tag new-gene-name tag was added to gene: TMEM251. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.14 | TMEM251 | Ida Ertmanska commented on gene: TMEM251: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.24 | TMEM251 | Ida Ertmanska commented on gene: TMEM251: Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.24 | TMEM251 | Ida Ertmanska Tag new-gene-name tag was added to gene: TMEM251. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.24 | TMEM251 | Ida Ertmanska Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156 to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156; lysosomal storage disease with skeletal involvement, MONDO:0800088 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.23 | TMEM251 | Ida Ertmanska edited their review of gene: TMEM251: Changed phenotypes to: Dysostosis multiplex, Ain-Naz type, OMIM:619345, dysostosis multiplex, Ain-Naz type, MONDO:0859156, lysosomal storage disease with skeletal involvement, MONDO:0800088 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.23 | TMEM251 | Ida Ertmanska Classified gene: TMEM251 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.23 | TMEM251 | Ida Ertmanska Added comment: Comment on list classification: There are now four unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, stemming from abnormal lysosomal enzyme activity. Hence, this gene can be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.23 | TMEM251 | Ida Ertmanska Gene: tmem251 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Arthrogryposis v10.14 | TMEM251 |
Ida Ertmanska gene: TMEM251 was added gene: TMEM251 was added to Arthrogryposis. Sources: Literature Q3_26_promote_green tags were added to gene: TMEM251. Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM251 were set to 33252156; 40171858; 41858182 Phenotypes for gene: TMEM251 were set to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156 Review for gene: TMEM251 was set to GREEN Added comment: PMID: 41858182 Sperb-Ludwig et al., 2026 Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more). PMID: 40171858 Kariminejad et al., 2025 Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD. PMID:33252156 Ain et al., 2021 Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities. Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family). Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes). Sources: Literature |
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| Likely inborn error of metabolism v9.22 | TMEM251 |
Ida Ertmanska gene: TMEM251 was added gene: TMEM251 was added to Likely inborn error of metabolism. Sources: Literature Q3_26_promote_green tags were added to gene: TMEM251. Mode of inheritance for gene: TMEM251 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM251 were set to 33252156; 40171858; 41858182 Phenotypes for gene: TMEM251 were set to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156 Review for gene: TMEM251 was set to GREEN Added comment: PMID: 41858182 Sperb-Ludwig et al., 2026 Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more). PMID: 40171858 Kariminejad et al., 2025 Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD. PMID:33252156 Ain et al., 2021 Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities. Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family). Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v6.12 | TMEM251 | Ida Ertmanska Classified gene: TMEM251 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v6.12 | TMEM251 | Ida Ertmanska Added comment: Comment on list classification: Updated rating to Amber as second patient reported in PMID:41858182 (brachycephaly). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v6.12 | TMEM251 | Ida Ertmanska Gene: tmem251 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 | TMEM251 | Ida Ertmanska reviewed gene: TMEM251: Rating: AMBER; Mode of pathogenicity: None; Publications: 41858182, 40171858; Phenotypes: Dysostosis multiplex, Ain-Naz type, OMIM:619345, craniosynostosis, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.31 | ZBTB20 | Ida Ertmanska Classified gene: ZBTB20 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.31 | ZBTB20 | Ida Ertmanska Gene: zbtb20 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.30 | ZBTB20 | Ida Ertmanska edited their review of gene: ZBTB20: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v9.30 | ZBTB20 | Ida Ertmanska changed review comment from: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.; to: Comment on list classification: As skeletal dysplasia is a relatively rare feature in Primrose syndrome patients (5 of more than 50 cases reported to have skeletal dysplasia), this gene should remain Amber on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.4 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.3 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.54 | ATP6AP2 | Ida Ertmanska Tag Q3_26_MOI tag was added to gene: ATP6AP2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.54 | ATP6AP2 | Ida Ertmanska commented on gene: ATP6AP2: Comment on mode of inheritance: As there is an affected female reported in literature with a heterozygous ATP6AP2 variant and intellectual disability, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.54 | ATP6AP2 | Ida Ertmanska reviewed gene: ATP6AP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11782983, 15746149, 26467484, 30985297, 38274877, 41131679; Phenotypes: Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, syndromic X-linked intellectual disability Hedera type, MONDO:0010319; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.34 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.21 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.33 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.20 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.24 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.7 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.6 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.17 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.17 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 | GPR15 |
Boaz Palterer gene: GPR15 was added gene: GPR15 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: GPR15 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: GPR15 were set to 42259915 Phenotypes for gene: GPR15 were set to Inflammatory bowel disease; IBD; VEOIBD Penetrance for gene: GPR15 were set to Incomplete Review for gene: GPR15 was set to RED Added comment: Cui et al. described multiple patients from multiple kindreds, harboring homozygous or compound heterozygous mutations in the GPR15 gene. They presented with severe early-onset inflammatory bowel disease. The underlying mechanism and phenotype were validated in vivo using complete Gpr15 knockout (KO) mouse models, demonstrating impaired colonic homing of regulatory CD8+ TIGR cells, an accumulation of inflammatory macrophages, and increased susceptibility to colitis. Sources: Literature |
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| Likely inborn error of metabolism v9.20 | ATP6AP2 | Eleanor Williams Entity copied from Congenital disorders of glycosylation v8.6 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Likely inborn error of metabolism v9.20 | ATP6AP2 |
Eleanor Williams gene: ATP6AP2 was added gene: ATP6AP2 was added to Likely inborn error of metabolism. Sources: Literature,Expert Review Amber Q3_26_promote_green tags were added to gene: ATP6AP2. Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: ATP6AP2 were set to 29127204; 38075676; 41131679 Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive Mode of pathogenicity for gene: ATP6AP2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments |
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| Cholestasis v4.16 | ATP6AP2 | Eleanor Williams Publications for gene: ATP6AP2 were set to 29127204; 41131679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.16 | ISCA-37417-Loss | Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed 9th July 2026 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v4.16 | ISCA-37417-Loss | Eleanor Williams Phenotypes for Region: ISCA-37417-Loss were changed from 308100; Ichthyosis, X-linked to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Proteinuric renal disease v6.9 | ISCA-37417-Loss | Eleanor Williams Phenotypes for Region: ISCA-37417-Loss were changed from Ichthyosis, X-linked, OMIM:308100 to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.54 | CAPRIN1 | Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636 to Neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder, OMIM:620782; Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.33 | CAPRIN1 | Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636 to Neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder, OMIM:620782 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.53 | SYP | Ida Ertmanska reviewed gene: SYP: Rating: AMBER; Mode of pathogenicity: None; Publications: 19377476, 24721225, 28887151, 32193494, 34310040; Phenotypes: Intellectual developmental disorder, X-linked 96, OMIM:300802; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 | ATP6AP2 | Ida Ertmanska Tag Q3_26_promote_green was removed from gene: ATP6AP2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 | ATP6AP2 | Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no recurrent infections noted. Hence, this gene should be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, based on cases with missense variants.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). However, only 2 probands presented with recurrent infections. Hence, this gene should remain Amber on Primary immunodeficiency or monogenic inflammatory bowel disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). Sources: Literature; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. No immunodeficiency noted. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). Sources: Literature |
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| Neurodegenerative disorders, adult onset v9.3 | ATP6AP2 | Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from ?Parkinsonism with spasticity, X-linked, OMIM:300911; Mental retardation, X-linked, syndromic, Hedera type, OMIM:300423 to ?Parkinsonism with spasticity, X-linked, OMIM:300911; Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dystonia, chorea or related movement disorder, adult onset v6.2 | ATP6AP2 | Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from ?Parkinsonism with spasticity, X-linked 300911; Mental retardation, X-linked, syndromic, Hedera type 300423 to ?Parkinsonism with spasticity, X-linked 300911; Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.53 | ATP6AP2 | Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423 syndromic X-linked intellectual disability Hedera type, MONDO:0010319 to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 | ATP6AP2 | Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.23 | ATP6AP2 | Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.22 | ATP6AP2 | Ida Ertmanska Mode of pathogenicity for gene: ATP6AP2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.21 | ATP6AP2 | Ida Ertmanska Publications for gene: ATP6AP2 were set to 29127204; 41131679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.20 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 | ATP6AP2 | Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no recurrent infections noted. Hence, this gene should be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, based on cases with missense variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 | ATP6AP2 | Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Liver features reported: early-onset cirrhosis and steatosis, neonatal liver failure, hepatosplenomegaly, liver transplant before 1 year of age. Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency, with early-onset recurrent infections). Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Liver features reported: early-onset cirrhosis and steatosis, neonatal liver failure, hepatosplenomegaly, liver transplant before 1 year of age. Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation.; Changed publications to: 29127204, 38075676, 41131679; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.15 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.15 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed publications to: 29127204, 38075676, 41131679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.15 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.14 | ATP6AP2 | Ida Ertmanska Mode of pathogenicity for gene: ATP6AP2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.13 | ATP6AP2 | Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.13 | ATP6AP2 | Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Liver features reported: early-onset cirrhosis and steatosis, neonatal liver failure, hepatosplenomegaly, liver transplant before 1 year of age. Patients with hemizygous splicing variants present with a different phenotype (DEE-type neurological presentation), with no liver involvement. Hence, this gene should be promoted to Green on Cholestasis, based on cases with missense variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cholestasis v4.13 | ATP6AP2 | Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). Sources: Literature |
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| Cholestasis v4.12 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). Sources: Literature |
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| Intellectual disability v10.52 | ATP6AP2 | Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from Mental retardation, X-linked, syndromic, Hedera type, 300423; MENTAL RETARDATION X-LINKED WITH EPILEPSY; X-linked intellectual disability, Hedera type to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423 syndromic X-linked intellectual disability Hedera type, MONDO:0010319 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.32 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation of p.Phe247_Ala286del. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). |
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| Early onset or syndromic epilepsy v9.32 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a male patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). |
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| Early onset or syndromic epilepsy v9.32 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed publications to: 11782983, 15746149, 26467484, 30985297, 38274877, 41131679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.32 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026).; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38274877 Liang et al., 2024 Report of a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G>A (p.Ala286=) variant. SpliceAI score = Splice-Altering / moderate (0.25). An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. Patient presentation: tonic seizures at 3.5 months of age, MRI indicated impaired brain white matter development and reduced left hippocampal volume. PMID: 30985297 Hirose et al., 2019 Study identified a de novo intronic ATP6AP2 variant c.301-11_301-10delTT in a boy with XLID and fulminant early postnatal neurodegeneration. He was diagnosed at the age of 2 weeks with seizures and mild facial dysmorphism, he developed intractable seizures and generalized limb spasticity. MRI showed rapidly decreasing cortical gray and white matter volumes, a thin, poorly developing corpus callosum, and myelination deficits. Variant is expected to increase exon 4 skipping - confirmed by RT-PCR (20% full-length ATP6AP2 (fl-ATP6AP2) and 80% ATP6AP2Δe4 transcripts). Other reports not curated in detail: PMID: 26467484 Gupta et al., 2015: 'A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism' PMID: 15746149 Ramser et al., 2005: 'A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor' PMID: 11782983 Hedera et al., 2002: 'Novel mental retardation-epilepsy syndrome linked to Xp21.1-p11.4' ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). |
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| Early onset or syndromic epilepsy v9.32 | ATP6AP2 | Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.32 | ATP6AP2 | Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 splicing variants (causing exon skipping), and presented with intellectual disability and early-onset severe epilepsy. Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.32 | ATP6AP2 | Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.31 | ATP6AP2 | Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319 to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.31 | ATP6AP2 | Ida Ertmanska Phenotypes for gene: ATP6AP2 were changed from Mental retardation, X-linked, syndromic, Hedera type to Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423; syndromic X-linked intellectual disability Hedera type, MONDO:0010319 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.30 | ATP6AP2 | Ida Ertmanska Publications for gene: ATP6AP2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.29 | ATP6AP2 |
Ida Ertmanska Tag watchlist was removed from gene: ATP6AP2. Tag Q3_26_promote_green tag was added to gene: ATP6AP2. |
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| Early onset or syndromic epilepsy v9.29 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed publications to: 26467484, 30985297, 41131679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.29 | ATP6AP2 | Ida Ertmanska reviewed gene: ATP6AP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30985297, 41131679; Phenotypes: Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, syndromic X-linked intellectual disability Hedera type, MONDO:0010319; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.6 | ATP6AP2 | Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype - a DEE-type neurological presentation. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation based on the cases with missense variants.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype (DEE-type neurological presentation), though glycosylation abnormalities were also seen in patient fibroblasts. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.6 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). Sources: Literature; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants (confirmed splicing effects by RNA-seq) and ID/DD, severe epilepsy (3 male patients), axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype (at 14yrs she had mild ID, autism, and progressive microcephaly). RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. No liver involvement in these 4 patients. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). Sources: Literature |
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| Congenital disorders of glycosylation v8.6 | ATP6AP2 | Ida Ertmanska Mode of inheritance for gene: ATP6AP2 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.5 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.5 | ATP6AP2 | Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype - a DEE-type neurological presentation. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation based on the cases with missense variants.; to: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype - a DEE-type neurological presentation. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation based on the cases with missense variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.5 | ATP6AP2 | Ida Ertmanska Publications for gene: ATP6AP2 were set to 29127204; 41131679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.4 | ATP6AP2 | Ida Ertmanska Mode of pathogenicity for gene: ATP6AP2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.3 | ATP6AP2 | Ida Ertmanska Classified gene: ATP6AP2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.3 | ATP6AP2 | Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated families reported in literature where individuals harboured hemizygous ATP6AP2 missense variants, and presented with a congenital disorder of glycosylation (primarily manifesting by liver disease and immunodeficiency). Patients with hemizygous nonsense variants present with a different phenotype - a DEE-type neurological presentation. Hence, this gene should be promoted to Green on Congenital disorders of glycosylation based on the cases with missense variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.3 | ATP6AP2 | Ida Ertmanska Gene: atp6ap2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.2 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. ATP6AP2 is associated with X-linked Congenital disorder of glycosylation, type IIr, OMIM:301045, Intellectual developmental disorder, X-linked syndromic, Hedera type, OMIM:300423, and ?Parkinsonism with spasticity, X-linked, OMIM:300911 (OMIM accessed 8th July 2026). Sources: Literature |
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| Congenital disorders of glycosylation v8.2 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.2 | ATP6AP2 | Ida Ertmanska edited their review of gene: ATP6AP2: Changed publications to: 29127204, 38075676, 41131679 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital disorders of glycosylation v8.2 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 38075676 Fang et al., 2023 Chinese patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 38075676 Fang et al., 2023 11mo Chinese male patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. He presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. Functional: metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature |
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| Congenital disorders of glycosylation v8.2 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 38075676 Fang et al., 2023 Chinese patient with a novel ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 38075676 Fang et al., 2023 Chinese patient with a novel hemizygous ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature |
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| Congenital disorders of glycosylation v8.2 | ATP6AP2 |
Ida Ertmanska changed review comment from: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature; to: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 38075676 Fang et al., 2023 Chinese patient with a novel ATP6AP2 variant c.185G>A (p.Gly62Glu) and a congenital disorder of glycosylation. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature |
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| Cholestasis v4.12 | ATP6AP2 |
Ida Ertmanska gene: ATP6AP2 was added gene: ATP6AP2 was added to Cholestasis. Sources: Literature Q3_26_promote_green tags were added to gene: ATP6AP2. Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: ATP6AP2 were set to 29127204; 41131679 Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive Review for gene: ATP6AP2 was set to GREEN Added comment: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.19 | ATP6AP2 |
Ida Ertmanska gene: ATP6AP2 was added gene: ATP6AP2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Q3_26_promote_green tags were added to gene: ATP6AP2. Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: ATP6AP2 were set to 29127204; 41131679 Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive Review for gene: ATP6AP2 was set to GREEN Added comment: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature |
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| Congenital disorders of glycosylation v8.2 | ATP6AP2 |
Ida Ertmanska gene: ATP6AP2 was added gene: ATP6AP2 was added to Congenital disorders of glycosylation. Sources: Literature Q3_26_promote_green tags were added to gene: ATP6AP2. Mode of inheritance for gene: ATP6AP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: ATP6AP2 were set to 29127204; 41131679 Phenotypes for gene: ATP6AP2 were set to Congenital disorder of glycosylation, type IIr, OMIM:301045; congenital disorder of glycosylation, type IIr, MONDO:0026765; congenital disorder of glycosylation, type IIr, X-linked recessive Review for gene: ATP6AP2 was set to GREEN Added comment: PMID: 41131679 Raynor et al., 2026 Authors identified three males and one female from three families with ATP6AP2 splicing variants and ID/DD, epilepsy, axial hypotonia, axonal neuropathy and microcephaly; the heterozygous female has a milder phenotype. RNA-Seq in patient-derived fibroblasts validated defective splicing, correlated with lowered ATP6AP2 protein levels in fibroblasts alongside glycosylation abnormalities. PMID: 29127204 Rujano et al., 2017 Report of 3 individuals from 2 families with two hemizygous missense mutations in ATP6AP2. Seq method: WES. P1 - Portuguese male, hemizygous for the ATP6AP2:c.293T>C (p.L98S) variant. Liver biopsy at 16 mo of age showing cirrhosis and steatosis; recurrent infections noted. P2, P3 - 2 males from a German family, hemizygous for a ATP6AP2:c.212G>A (p.R71H) variant. P2: recurrent pulmonary and upper respiratory tract infections throughout infancy and childhood; ultrasounds showed hepatosplenomegaly. P3: developed liver failure at 5 months of age, liver biopsy revealed lipid accumulation and enlarged vacuolar structures within hepatocytes; suffered from recurrent infections. Functional: Authors also show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. Sources: Literature |
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| Intellectual disability v10.51 | UNC79 | Ida Ertmanska Classified gene: UNC79 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.51 | UNC79 | Ida Ertmanska Added comment: Comment on list classification: There are 5 unrelated individuals reported in literature with heterozygous de novo UNC79 variants and a neurodevelopmental disorder, including intellectual disability (mild to moderate). Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.51 | UNC79 | Ida Ertmanska Gene: unc79 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.29 | UNC79 | Ida Ertmanska Classified gene: UNC79 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.29 | UNC79 | Ida Ertmanska Added comment: Comment on list classification: There are 4 unrelated individuals reported in literature with heterozygous de novo UNC79 variants and syndromic epilepsy. Hence, this gene should be promoted to Green at the next update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v9.29 | UNC79 | Ida Ertmanska Gene: unc79 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v10.50 | UNC79 |
Ida Ertmanska changed review comment from: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia. Sources: Literature; to: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Sequencing method: trio WES (5 individuals) / duo WES (1). Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia. Sources: Literature |
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| Early onset or syndromic epilepsy v9.28 | UNC79 |
Ida Ertmanska changed review comment from: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia. Sources: Literature; to: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Sequencing method: trio WES (5 individuals) / duo WES (1). Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia. Sources: Literature |
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| Early onset or syndromic epilepsy v9.28 | UNC79 |
Ida Ertmanska changed review comment from: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. Sources: Literature; to: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia. Sources: Literature |
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| Intellectual disability v10.50 | UNC79 |
Ida Ertmanska changed review comment from: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. Sources: Literature; to: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. UNC79 is Green on Intellectual disability syndromic and non-syndromic and Genetic epilepsy panels in PanelApp Australia. Sources: Literature |
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| Early onset or syndromic epilepsy v9.28 | UNC79 |
Ida Ertmanska gene: UNC79 was added gene: UNC79 was added to Early onset or syndromic epilepsy. Sources: Literature Q3_26_promote_green tags were added to gene: UNC79. Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UNC79 were set to 37183800 Phenotypes for gene: UNC79 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: UNC79 was set to GREEN Added comment: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. Sources: Literature |
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| Intellectual disability v10.50 | UNC79 |
Ida Ertmanska gene: UNC79 was added gene: UNC79 was added to Intellectual disability. Sources: Literature Q3_26_promote_green tags were added to gene: UNC79. Mode of inheritance for gene: UNC79 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: UNC79 were set to 37183800 Phenotypes for gene: UNC79 were set to neurodevelopmental disorder, MONDO:0700092 Review for gene: UNC79 was set to GREEN Added comment: PMID: 37183800 Bayat et al., 2023 Study reports 6 unrelated individuals with heterozygous UNC79 variants. Phenotypic spectrum: - 4/6 autistic features - 5/6 patients mild-moderate ID - 4/6 behavioural issues (aggression, stereotypies) - 4/6 epilepsy (focal / tonic-clonic seizures) - 5/6 hypotonia Functional evidence: Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a het LoF variant have a developmental delay in body weight compared with WT mice. In addition, they have impaired ability in learning and memory. This gene is not yet associated with disease in OMIM or ClinGen, and there is a Limited association between UNC79 and UNC79-related intellectual disability with focal motor seizures (monoallelic LoF) in G2P. Sources: Literature |
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