Activity

Filter

Cancel
Date Panel Item Activity
3000 actions
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
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
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
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.
Adult onset dystonia, chorea or related movement disorder 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
Adult onset dystonia, chorea or related movement disorder 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
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
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
Adult onset neurodegenerative disorder 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
Adult onset dystonia, chorea or related movement disorder 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
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
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).
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).
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).
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Early onset or syndromic epilepsy v9.27 SHANK3 Ida Ertmanska Classified gene: SHANK3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.27 SHANK3 Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals reported in literature with heterozygous SHANK3 variants and Phelan-McDermid syndrome. Around 30% of patients reported to date had seizures. Hence, this gene should be promoted to Green on Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v9.27 SHANK3 Ida Ertmanska Gene: shank3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.26 SHANK3 Ida Ertmanska gene: SHANK3 was added
gene: SHANK3 was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_26_promote_green tags were added to gene: SHANK3.
Mode of inheritance for gene: SHANK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SHANK3 were set to 29719671; 36967043
Phenotypes for gene: SHANK3 were set to Phelan-McDermid syndrome, OMIM:606232; Phelan-McDermid syndrome, MONDO:0011652
Review for gene: SHANK3 was set to GREEN
Added comment: PMID: 29719671 De Rubeis et al., 2018
Report of 17 individuals with Phelan-McDermid syndrome, and literature review of 60 other previously reported patients. Most mutations were truncating, often de novo, with 4 recurrent variants p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A. Seizures were present in 5/17 individuals (29%).

PMID: 36967043 de Coo et al., 2023
Publication is part of European guidelines for Phelan-McDermid syndrome (PMS). In the largest cohort of PMS patients (n=201), prevalence of seizures was 27%. The prevalence goes up with age e.g., seizure onset under age 5yrs was 11%, but 43% between ages 10-18yrs. Pooled prevalence of seizures from 14 PMS studies was 32%. All types of seizures, febrile and non-febrile, have been recorded.
Sources: Literature
Fetal anomalies v7.28 ZBTB20 Arina Puzriakova Phenotypes for gene: ZBTB20 were changed from PRIMROSE SYNDROME to Primrose syndrome, OMIM:259050
Intellectual disability v10.49 ZBTB20 Arina Puzriakova Phenotypes for gene: ZBTB20 were changed from PRIMROSE SYNDROME to Primrose syndrome, OMIM:259050
Adult onset neurodegenerative disorder v9.2 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

PMID: 31312839 Lee et al., 2019
Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor.
Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort).
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

PMID: 31312839 Lee et al., 2019
Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor.
Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort).
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.
Congenital hyperinsulinism v3.9 CACNA1C Sarah Flanagan reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 30067485, PMID: 35897673, PMID: 39420001; Phenotypes: Congenital Hyperinsulinism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska commented on gene: ARSA: Comment on list classification: ARSA deficiency is a well-established cause of recessive metachromatic leukodystrophy. There is also some emerging evidence that heterozygous variants in ARSA may be a genetic modifier of Parkinson's disease. However, heterozygous variants act as risk factors, rather than causing familial dominant disease. Hence, the mode of inheritance should remain as 'BIALLELIC, autosomal or pseudoautosomal' on this panel.
Likely inborn error of metabolism v9.19 ARSA Ida Ertmanska Phenotypes for gene: ARSA were changed from Metachromatic leukodystrophy to Metachromatic leukodystrophy, OMIM:250100; metachromatic leukodystrophy, MONDO:0018868; arylsulfatase A deficiency
Intellectual disability v10.48 ARSA Ida Ertmanska Phenotypes for gene: ARSA were changed from ARYLSULFATASE A DEFICIENCY to Metachromatic leukodystrophy, OMIM:250100; metachromatic leukodystrophy, MONDO:0018868; arylsulfatase A deficiency
Adult onset neurodegenerative disorder v9.2 ARSA Ida Ertmanska commented on gene: ARSA: Comment on mode of inheritance: ARSA deficiency is a well-established cause of recessive metachromatic leukodystrophy. There is also some emerging evidence that heterozygous variants in ARSA may be a genetic modifier of Parkinson's disease. However, heterozygous variants act as risk factors, rather than causing familial dominant disease. Hence, the mode of inheritance should remain as 'BIALLELIC, autosomal or pseudoautosomal' on this panel.
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska edited their review of gene: ARSA: Changed phenotypes to: Metachromatic leukodystrophy, OMIM:250100, metachromatic leukodystrophy, MONDO:0018868, arylsulfatase A deficiency
Adult onset neurodegenerative disorder v9.2 ARSA Ida Ertmanska reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31312839, 37381728; Phenotypes: Metachromatic leukodystrophy, OMIM:250100, metachromatic leukodystrophy, MONDO:0018868, arylsulfatase A deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska edited their review of gene: ARSA: Changed phenotypes to: Metachromatic leukodystrophy, OMIM:250100
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

p.L300V variant found in two cases and one controls

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

PMID: 31312839 Lee et al., 2019
Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor.
Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort).
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

p.L300V variant found in two cases and one control

Also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. However, one of the patients, II-4 from the first family, was also a carrier of the GBA1 variant RecNcil - which impossible to estimate the role of the ARSA variant in PD. The variant was not found in any controls.
Caveat: the variant is referred to as p.E382K and p.E384K in different parts of the publication. Likely to be the c.1150G>A, p.Glu384Lys variant - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

p.L300V variant found in two cases and one controls

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

p.L300V variant found in two cases and one control

Also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. However, one of the patients, II-4 from the first family, was also a carrier of the GBA1 variant RecNcil - which impossible to estimate the role of the ARSA variant in PD. The variant was not found in any controls.
Caveat: the variant is referred to as p.E382K and p.E384K in different parts of the publication. Likely to be the c.1150G>A, p.Glu384Lys variant - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska reviewed gene: ARSA: Rating: AMBER; Mode of pathogenicity: None; Publications: 31312839, 37381728; Phenotypes: Menkes disease, OMIM:309400, Neuronopathy, distal hereditary motor, X-linked, OMIM:300489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Proteinuric renal disease v6.8 STS Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease. ; to: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease. Instead, the ISCA-37417-Loss (Xp22.31 recurrent region (includes STS) Loss) has been suggested for promotion to Green on this panel.
Proteinuric renal disease v6.8 ISCA-37417-Loss Ida Ertmanska Classified Region: ISCA-37417-Loss as Amber List (moderate evidence)
Proteinuric renal disease v6.8 ISCA-37417-Loss Ida Ertmanska Added comment: 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.
Proteinuric renal disease v6.8 ISCA-37417-Loss Ida Ertmanska Region: isca-37417-loss has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v6.7 ISCA-37417-Loss Ida Ertmanska Region: ISCA-37417-Loss was added
Region: ISCA-37417-Loss was added to Proteinuric renal disease. Sources: Literature
Q3_26_expert_review, Q3_26_promote_green tags were added to Region: ISCA-37417-Loss.
Mode of inheritance for Region: ISCA-37417-Loss was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for Region: ISCA-37417-Loss were set to 17468528; 22419362; 23939749; 29672931; 35115028
Phenotypes for Region: ISCA-37417-Loss were set to Ichthyosis, X-linked, OMIM:308100
Review for Region: ISCA-37417-Loss was set to GREEN
Added comment: PMID: 17468528 Krishnamurthy, Kapoor, and Yadav, 2007
Reported a 4yo proband with ichthyosis and a steroid-resistant nephrotic syndrome. Generalised edema and proteinuria of 4.25g/day were noted. Many male family members also had ichthyosis. Renal biopsy showed no segmental sclerosis, tubular atrophy, fibrosis, or deposits; diagnosed with minimal change disease. STS deletion detected by multiplex PCR (targeted STS gene specifically).

PMID: 22419362 Mishra et al., 2012
Report of a 4yo boy with steroid-resistant nephrotic syndrome (SRNS) with an underlying ichthyotic skin present since birth. Genetic analysis showed full deletion of the STS gene.

PMID: 23939749 Song et al., 2013
12yo male patient with X-linked ichthyosis (XLI) in association with glomerular sclerosis. Complete deletion of STS and flanking regions was detected. Renal features: renal failure, anemia, hypocalcemia, mild proteinuria (0.4g/day). Uncles also affected by ichthyosis and short stature. Authors highlight that it is unknown whether STS or the flanking regions were causal in the renal presentation.

PMID: 29672931 Diociaiuti et al., 2019
Cohort of 35 Italian male patients with X-linked ichthyosis. 27 patients showed complete STS deletion - 1 de novo, others maternally inherited. 7 patients had microdeletions of 1.3-1.6Mb, and 2 patients had large deletions of 8.2 and 9.7Mb - resulting in contiguous gene syndrome. Lastly, 7 individuals from 4 unrelated families had 4 different missense mutations in STS. Seq method: MLPA + ichthyosis NGS panel. Apart from cutaneous changes, other findings included cryptorchidism, neuropsychiatric findings, motor disabilities. No mention of renal disease. Authors note that only 10% of patients have point mutations in STS, with majority of cases harbouring STS deletions.

PMID: 35115028 Schierz et al., 2022
Male newborn with CAKUT with kidney failure and progressive vomiting. "Comparative whole-genome hybridization detected a maternal inherited interstitial deletion of 1.56 Mb on Xp22.31(6,552,712_8,115,153) × 0 involving the STS gene, but not the KAL1 gene." Other affected genes: VCX, PUDP, PNPLA4, as well as microRNAs MIR4767 and MIR651.
Sources: Literature
Proteinuric renal disease v6.6 STS Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease. ; to: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease.
Proteinuric renal disease v6.6 STS Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuria. ; to: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuric renal disease.
Proteinuric renal disease v6.6 STS Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline and STS should remain Amber for Proteinuria.; to: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline. SNVs have been reported in this gene (about 10% of cases), but the individuals did not have renal disease. Hence, STS should remain Amber for Proteinuria.
Proteinuric renal disease v6.6 STS Ida Ertmanska edited their review of gene: STS: Changed rating: AMBER
Proteinuric renal disease v6.6 STS Ida Ertmanska Classified gene: STS as Amber List (moderate evidence)
Proteinuric renal disease v6.6 STS Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported with renal disease (CAKUT, nephrotic syndrome, proteinuria) and deletions that encompass the STS gene. However, these structural variants would not be detected in the current NGS analysis pipeline and STS should remain Amber for Proteinuria.
Proteinuric renal disease v6.6 STS Ida Ertmanska Gene: sts has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v6.5 STS Ida Ertmanska edited their review of gene: STS: Changed publications to: 17468528, 22419362, 23939749, 29672931, 35115028
Proteinuric renal disease v6.5 STS Ida Ertmanska changed review comment from: PMID: 17468528 Krishnamurthy, Kapoor, and Yadav, 2007
Reported a 4yo proband with ichthyosis and a steroid-resistant nephrotic syndrome. Generalised edema and proteinuria of 4.25g/day were noted. Many male family members also had ichthyosis. Renal biopsy showed no segmental sclerosis, tubular atrophy, fibrosis, or deposits; diagnosed with minimal change disease. STS deletion detected by multiplex PCR (targeted STS gene specifically).

PMID: 22419362 Mishra et al., 2012
Report of a 4yo boy with steroid-resistant nephrotic syndrome (SRNS) with an underlying ichthyotic skin present since birth. Genetic analysis showed full deletion of the STS gene.

PMID: 23939749 Song et al., 2013
12yo male patient with X-linked ichthyosis (XLI) in association with glomerular sclerosis. Complete deletion of STS and flanking regions was detected. Renal features: renal failure, anemia, hypocalcemia, mild proteinuria (0.4g/day). Uncles also affected by ichthyosis and short stature. Authors highlight that it is unknown whether STS or the flanking regions were causal in the renal presentation.

PMID: 35115028 Schierz et al., 2022
Male newborn with CAKUT with kidney failure and progressive vomiting. "Comparative whole-genome hybridization detected a maternal inherited interstitial deletion of 1.56 Mb on Xp22.31(6,552,712_8,115,153) × 0 involving the STS gene, but not the KAL1 gene." Other affected genes: VCX, PUDP, PNPLA4, as well as microRNAs MIR4767 and MIR651.; to: PMID: 17468528 Krishnamurthy, Kapoor, and Yadav, 2007
Reported a 4yo proband with ichthyosis and a steroid-resistant nephrotic syndrome. Generalised edema and proteinuria of 4.25g/day were noted. Many male family members also had ichthyosis. Renal biopsy showed no segmental sclerosis, tubular atrophy, fibrosis, or deposits; diagnosed with minimal change disease. STS deletion detected by multiplex PCR (targeted STS gene specifically).

PMID: 22419362 Mishra et al., 2012
Report of a 4yo boy with steroid-resistant nephrotic syndrome (SRNS) with an underlying ichthyotic skin present since birth. Genetic analysis showed full deletion of the STS gene.

PMID: 23939749 Song et al., 2013
12yo male patient with X-linked ichthyosis (XLI) in association with glomerular sclerosis. Complete deletion of STS and flanking regions was detected. Renal features: renal failure, anemia, hypocalcemia, mild proteinuria (0.4g/day). Uncles also affected by ichthyosis and short stature. Authors highlight that it is unknown whether STS or the flanking regions were causal in the renal presentation.

PMID: 29672931 Diociaiuti et al., 2019
Cohort of 35 Italian male patients with X-linked ichthyosis. 27 patients showed complete STS deletion - 1 de novo, others maternally inherited. 7 patients had microdeletions of 1.3-1.6Mb, and 2 patients had large deletions of 8.2 and 9.7Mb - resulting in contiguous gene syndrome. Lastly, 7 individuals from 4 unrelated families had 4 different missense mutations in STS. Seq method: MLPA + ichthyosis NGS panel. Apart from cutaneous changes, other findings included cryptorchidism, neuropsychiatric findings, motor disabilities. No mention of renal disease. Authors note that only 10% of patients have point mutations in STS, with majority of cases harbouring STS deletions.

PMID: 35115028 Schierz et al., 2022
Male newborn with CAKUT with kidney failure and progressive vomiting. "Comparative whole-genome hybridization detected a maternal inherited interstitial deletion of 1.56 Mb on Xp22.31(6,552,712_8,115,153) × 0 involving the STS gene, but not the KAL1 gene." Other affected genes: VCX, PUDP, PNPLA4, as well as microRNAs MIR4767 and MIR651.
Proteinuric renal disease v6.5 STS Ida Ertmanska Phenotypes for gene: STS were changed from Proteinuria; ichthyosis to Ichthyosis, X-linked, OMIM:308100
Proteinuric renal disease v6.4 STS Ida Ertmanska Publications for gene: STS were set to 22419362; 17468528
Proteinuric renal disease v6.3 STS Ida Ertmanska Mode of inheritance for gene: STS was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Proteinuric renal disease v6.2 STS Ida Ertmanska reviewed gene: STS: Rating: RED; Mode of pathogenicity: None; Publications: 17468528, 22419362, 23939749, 35115028; Phenotypes: Ichthyosis, X-linked, OMIM:308100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Skeletal dysplasia v9.30 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.; 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.
Skeletal dysplasia v9.30 TMEM251 Ida Ertmanska Classified gene: TMEM251 as Amber List (moderate evidence)
Skeletal dysplasia v9.30 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. Hence, this gene can be promoted to Green at the next update.
Skeletal dysplasia v9.30 TMEM251 Ida Ertmanska Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.29 TMEM251 Ida Ertmanska Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex, Ain-Naz type, OMIM:19345; severe short stature to Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156
Skeletal dysplasia v9.28 TMEM251 Ida Ertmanska Publications for gene: TMEM251 were set to 33252156
Skeletal dysplasia v9.27 TMEM251 Ida Ertmanska Mode of pathogenicity for gene: TMEM251 was changed from None to None
Skeletal dysplasia v9.26 TMEM251 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: TMEM251.
Skeletal dysplasia v9.26 TMEM251 Ida Ertmanska reviewed gene: TMEM251: Rating: GREEN; Mode of pathogenicity: None; Publications: 40171858, 41858182; Phenotypes: Dysostosis multiplex, Ain-Naz type, OMIM:619345, dysostosis multiplex, Ain-Naz type, MONDO:0859156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v6.28 ZBTB20 Ida Ertmanska Publications for gene: ZBTB20 were set to 32473227
Monogenic hearing loss v6.27 ZBTB20 Ida Ertmanska Classified gene: ZBTB20 as Amber List (moderate evidence)
Monogenic hearing loss v6.27 ZBTB20 Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals (at least 36) reported in literature with de novo heterozygous ZBTB20 variants and hearing loss. Hence, this gene can be promoted to Green at the next update.
Monogenic hearing loss v6.27 ZBTB20 Ida Ertmanska Gene: zbtb20 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: ZBTB20.
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska changed review comment from: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature; to: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).

https://www.ncbi.nlm.nih.gov/books/NBK570205/ - Primrose syndrome GeneReviews entry mentions 52 reported individuals. Skeletal abnormalities are not noted to be the main characteristic features. Some patients present with scoliosis and skull specific abormalities e.g., wormian bones, without wider skeletal involvement. The primary features consistent in most cases are: intellectual disability (100%), hearing loss (83%), dysmorphic facial features (>70%), hypotonia (76%), and autism (70%), with many other less specific features.

ZBTB20 is associated with AD Primrose syndrome, OMIM:259050 (OMIM accessed 7th July 2026).
Sources: Literature
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska edited their review of gene: ZBTB20: Changed rating: GREEN
Skeletal dysplasia v9.26 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 Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.
Skeletal dysplasia v9.26 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 Red on this panel. R27 Paediatric disorders is a more suitable Clinical Indication for this multisystemic disorder.
Skeletal dysplasia v9.26 ZBTB20 Ida Ertmanska edited their review of gene: ZBTB20: Changed rating: RED
Skeletal dysplasia v9.26 ZBTB20 Ida Ertmanska Classified gene: ZBTB20 as Red List (low evidence)
Skeletal dysplasia v9.26 ZBTB20 Ida Ertmanska Gene: zbtb20 has been classified as Red List (Low Evidence).
Skeletal dysplasia v9.25 ZBTB20 Ida Ertmanska Classified gene: ZBTB20 as Amber List (moderate evidence)
Skeletal dysplasia v9.25 ZBTB20 Ida Ertmanska Added comment: 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.
Skeletal dysplasia v9.25 ZBTB20 Ida Ertmanska Gene: zbtb20 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.24 ZBTB20 Ida Ertmanska Publications for gene: ZBTB20 were set to 32473227
Skeletal dysplasia v9.23 ZBTB20 Ida Ertmanska changed review comment from: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature; to: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).

https://www.ncbi.nlm.nih.gov/books/NBK570205/ - Primrose syndrome GeneReviews entry mentions 52 reported individuals. Skeletal abnormalities are not noted to be the main characteristic features. Some patients present with scoliosis and skull specific abormalities e.g., wormian bones, without wider skeletal involvement. The primary features consistent in most cases are: intellectual disability (100%), hearing loss (83%), dysmorphic facial features (>70%), hypotonia (76%), and autism (70%), with many other less specific features.

ZBTB20 is associated with AD Primrose syndrome, OMIM:259050 (OMIM accessed 7th July 2026).

Sources: Literature
Skeletal dysplasia v9.23 ZBTB20 Ida Ertmanska edited their review of gene: ZBTB20: Changed publications to: 31321892, 32473227
Monogenic hearing loss v6.26 ZBTB20 Ida Ertmanska gene: ZBTB20 was added
gene: ZBTB20 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB20 were set to 32473227
Phenotypes for gene: ZBTB20 were set to Primrose syndrome, OMIM:259050; Primrose syndrome, MONDO:0009798; intellectual disability-cataracts-calcified pinnae-myopathy syndrome
Review for gene: ZBTB20 was set to AMBER
Added comment: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature
Skeletal dysplasia v9.23 ZBTB20 Ida Ertmanska gene: ZBTB20 was added
gene: ZBTB20 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZBTB20 were set to 32473227
Phenotypes for gene: ZBTB20 were set to Primrose syndrome, OMIM:259050; Primrose syndrome, MONDO:0009798; intellectual disability-cataracts-calcified pinnae-myopathy syndrome
Review for gene: ZBTB20 was set to AMBER
Added comment: PMID: 31321892 Ferreira et al., 2019
P1 - male proband of European ancestry with Primrose syndrome: macrocephaly, hypoplasia of CC, mild kyphosis and multiple wormian bones, GDD. Trio WES detected a de novo ZBTB20 c.1822T>C, p.Cys608Arg variant.
P2 - male patient, Brazilian, with Primrose syndrome: GDD, strabismus, distal muscle wasting, ASD, hearing impairment, brain and ear calcifications seen on CT & MRI, dysmorphic features. Targeted ZBTB20 seq detected a c.1873A>G, p.Met625Val variant - not detected in the mother of siblings, father's DNA unavailable. No skeletal abnormalities apart from lumbar hyperlordosis.

PMID: 32473227 Arora et al., 2020
Report of 5 probands (all male, aged 2-23 yrs at time of report) with Primrose syndrome, one each from India, Japan, Europe, Lebanon and Africa. 4 families were noted to be non-consanguineous and 1 unspecified.
All 5 patients carried de novo heterozygous missense variants in ZBTB20: p.Thr627Ala, p.Cys639Tyr, p.His600Gln, p.Leu621Phe, & p.Cys639Tyr.
Phenotypic spectrum: learning disability (5/5), facial dysmorphism (5/5), macrocephaly (4/5), hearing loss (3/5), corpus callosum abnormality on MRI (2/5). In addition, all 5 probands had skeletal features: Wormian bones (5/5), Epiphyseal abnormalities (5/5), notably slender bones (5/5), spine involvement (3/5).
Sources: Literature
Early onset or syndromic epilepsy v9.25 BCL11A Ida Ertmanska changed review comment from: Comment on list classification: There are at least 13 unrelated patients with heterozygous BCL11A variants and early-onset epilepsy. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are at least 13 unrelated patients with heterozygous BCL11A variants and early-onset epilepsy (as part of Dias-Logan syndrome spectrum). Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.25 BCL11A Ida Ertmanska Classified gene: BCL11A as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.25 BCL11A Ida Ertmanska Added comment: Comment on list classification: There are at least 13 unrelated patients with heterozygous BCL11A variants and early-onset epilepsy. Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.25 BCL11A Ida Ertmanska Gene: bcl11a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska changed review comment from: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with heterozygous BCL11A variants had seizures, with median age of onset of 3 years.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature; to: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with heterozygous BCL11A variants had seizures, with median age of onset of 3 years. In 33/40 cases with inheritance information, the het variants were confirmed de novo. DD/IDD was noted in 97% of individuals reported, though severity varied. Only 17% of the cases had severe/profound ID.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska changed review comment from: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with biallelic BCL11A variants had seizures, with median age of onset of 3 years.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature; to: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with heterozygous BCL11A variants had seizures, with median age of onset of 3 years.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska changed review comment from: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with biallelic BCL11A variants had seizures, with median age of onset of 3 years.

PMID: 39835253 Shu et al., 2025
Report of an 8-year-old Han Chinese male patient with Dias-Logan syndrome who carries a de novo heterozygous pathogenic variant, c.1078dupC (p.Leu360Profs*212), in the BCL11A gene, leading to ID and γ-globin suppression, identified through trio-WES.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature; to: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with biallelic BCL11A variants had seizures, with median age of onset of 3 years.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska edited their review of gene: BCL11A: Changed publications to: 28589569, 32903878, 39448799
Early onset or syndromic epilepsy v9.24 BCL11A Ida Ertmanska gene: BCL11A was added
gene: BCL11A was added to Early onset or syndromic epilepsy. Sources: Literature
Q3_26_promote_green tags were added to gene: BCL11A.
Mode of inheritance for gene: BCL11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCL11A were set to 28589569; 32903878; 39835253
Phenotypes for gene: BCL11A were set to Dias-Logan syndrome, OMIM:617101; Dias-Logan syndrome, MONDO:0014914; BCL11A-related intellectual developmental disorder with persistence of fetal hemoglobin
Review for gene: BCL11A was set to GREEN
Added comment: PMID: 28589569 Yoshida et al., 2018
2 probands with heterozygous de novo BCL11A variants (c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr)), with an epileptic encephalopathy. Seq method: WES.
P1 - diagnosed with Lennox-Gastaut syndrome, seizure onset at 3yo; severe ID; head circumference at 14yrs was -2.6SD; no abnormalities on MRI
P2 - diagnosed with West syndrome, seizure onset at 2 months old; profound ID; head circumference at 9yrs was -2.1SD; thin corpus callosum noted on MRI

PMID: 32903878 Korenke et al., 2020
Report of a male proband with a de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene. He presented with ID, generalised idiopathic epilepsy, and severe language delay. First presented with motor development delay and muscle hypotonia at 9 months old; epilepsy diagnosed at 40 months.

PMID: 39448799 Peron et al., 2024 - lit review
25% of cases (13/53 patients) with biallelic BCL11A variants had seizures, with median age of onset of 3 years.

PMID: 39835253 Shu et al., 2025
Report of an 8-year-old Han Chinese male patient with Dias-Logan syndrome who carries a de novo heterozygous pathogenic variant, c.1078dupC (p.Leu360Profs*212), in the BCL11A gene, leading to ID and γ-globin suppression, identified through trio-WES.

BCL11A is associated with AD Dias-Logan syndrome, OMIM:617101 (OMIM accessed 7th July 2026).
Sources: Literature
DDG2P v7.8 BCL11A Ida Ertmanska Phenotypes for gene: BCL11A were changed from INTELLECTUAL DISABILITY to BCL11A-related intellectual disability; Dias-Logan syndrome, OMIM:617101
Intellectual disability v10.47 BCL11A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 7th July 2026
Intellectual disability v10.47 BCL11A Ida Ertmanska Phenotypes for gene: BCL11A were changed from INTELLECTUAL DISABILITY to Dias-Logan syndrome, OMIM:617101; Dias-Logan syndrome, MONDO:0014914; BCL11A-related intellectual developmental disorder with persistence of fetal hemoglobin
Fetal anomalies v7.27 BCL11A Ida Ertmanska Phenotypes for gene: BCL11A were changed from INTELLECTUAL DISABILITY to Dias-Logan syndrome, OMIM:617101; Dias-Logan syndrome, MONDO:0014914; BCL11A-related intellectual developmental disorder with persistence of fetal hemoglobin
Proteinuric renal disease v6.2 WDR4 John Sayer gene: WDR4 was added
gene: WDR4 was added to Proteinuric renal disease. Sources: Expert list
Mode of inheritance for gene: WDR4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR4 were set to 30079490; 40533795
Phenotypes for gene: WDR4 were set to growth deficiency; microcephaly; developmental delay; intellectual disability; proteinuria; nephrotic syndrome
Penetrance for gene: WDR4 were set to Complete
Review for gene: WDR4 was set to RED
Added comment: Additional case report not on pubmed 10.5734/jgm.2020.17.2.97
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v9.10 ATP6V0C Lucy Jackson reviewed gene: ATP6V0C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inherited polyposis and early onset colorectal cancer - germline testing v4.2 MSH3 Achchuthan Shanmugasundram Tag Q3_25_expert_review tag was added to gene: MSH3.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 ZBTB7B Boaz Palterer gene: ZBTB7B was added
gene: ZBTB7B was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB7B were set to 40392549
Phenotypes for gene: ZBTB7B were set to CD4+ T-cell deficiency; Allergic disease; Interstitial lung disease; Corneal neovascularization; Corneal scarring; Global developmental delay; Growth failure
Penetrance for gene: ZBTB7B were set to unknown
Review for gene: ZBTB7B was set to RED
Added comment: Vaseghi-Shanjani et al. described 1 patient from 1 kindred, harboring a de novo heterozygous mutation in the ZBTB7B gene encoding ThPOK. They presented with persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The underlying mechanism and phenotype were validated in vitro using lentivirally transduced healthy control T cells and fibroblasts, demonstrating impaired T cell receptor activation and increased profibrotic gene expression. The study did not specify whether the phenotype was successfully recreated with complete knockout (KO) models or if the defect was corrected via rescue experiments.
Sources: Literature
Intellectual disability v10.46 WAC Ida Ertmanska Phenotypes for gene: WAC were changed from Paper out in august to Desanto-Shinawi syndrome, OMIM:616708; WAC-related facial dysmorphism-developmental delay-behavioral abnormalities syndrome; DeSanto-Shinawi syndrome, MONDO:0018760
Hereditary neuropathy or pain disorder v8.9 MT-TV Christopher Record reviewed gene: MT-TV: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32715519, 38371303, 39468830, 39243325; Phenotypes: Peripheral neuropathy, spasticity; Mode of inheritance: MITOCHONDRIAL
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFB Ida Ertmanska Tag Q2_26_promote_green was removed from gene: CFB.
Monogenic hearing loss v6.25 DSPP Ida Ertmanska changed review comment from: Comment on list classification: There is limited and conflicting evidence regarding the association between DSPP variants and dominant hearing loss. There are 3 Chinese families reported with DSPP missense variants and hearing loss, including one pedigree with a common likely benign variant. The other two families had both dentinogenesis imperfecta and hearing loss, and harboured the same DSPP variant detected by linkage analysis/targeted DSPP seq - another gene likely responsible for hearing loss. In addition, numerous other cases with 59+ different DSPP variants have been reported in literature with isolated dentinogenesis imperfecta.; to: Comment on list classification: There is limited and conflicting evidence regarding the association between DSPP variants and dominant hearing loss. There are 3 Chinese families reported with DSPP missense variants and hearing loss, including one pedigree with a common likely benign variant. The other two families had both dentinogenesis imperfecta and hearing loss, and harboured the same DSPP variant detected by linkage analysis/targeted DSPP seq - another gene likely responsible for hearing loss. In addition, numerous other cases with 59+ different DSPP variants have been reported in literature with isolated dentinogenesis imperfecta. As this is a demotion from Green rating, this gene is tagged for expert review.
Monogenic hearing loss v6.25 DSPP Ida Ertmanska Tag Q2_26_expert_review tag was added to gene: DSPP.
Fetal anomalies v7.26 NPR2 Achchuthan Shanmugasundram Phenotypes for gene: NPR2 were changed from ACROMESOMELIC DYSPLASIA MAROTEAUX TYPE to Short stature with nonspecific skeletal abnormalities, OMIM:616255
Fetal anomalies v7.25 NPR2 Achchuthan Shanmugasundram Publications for gene: NPR2 were set to
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.14 CFH Ida Ertmanska Tag Q2_26_MOI was removed from gene: CFH.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.14 CFH Ida Ertmanska changed review comment from: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported more than 30 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 21 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.; to: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported more than 30 individuals with rare monoallelic CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 21 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.
Likely inborn error of metabolism v9.18 PTPMT1 Arina Puzriakova Tag Q2_26_NHS_review was removed from gene: PTPMT1.
Likely inborn error of metabolism v9.18 PTPMT1 Arina Puzriakova Entity copied from Mitochondrial disorders v10.11
Likely inborn error of metabolism v9.18 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Likely inborn error of metabolism. Sources: Expert Review Amber,Literature
Q2_26_promote_green, Q2_26_expert_review, Q2_26_NHS_review tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova edited their review of gene: PTPMT1: Changed phenotypes to: Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Possible mitochondrial disorder - nuclear genes v5.10 PTPMT1 Arina Puzriakova edited their review of gene: PTPMT1: Changed phenotypes to: Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Possible mitochondrial disorder - nuclear genes v5.10 PTPMT1 Arina Puzriakova Tag watchlist was removed from gene: PTPMT1.
Tag Q2_26_promote_green tag was added to gene: PTPMT1.
Tag Q2_26_expert_review tag was added to gene: PTPMT1.
Possible mitochondrial disorder - nuclear genes v5.10 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v5.10 PTPMT1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England Clinical Team (William Macken and Helen Brittain) it was decided that it may be possible to classify this gene as green given the reasonably extensive functional work (further outlined below); however, inclusion should first be reviewed by the GMS expert team. As the phenotype is nonspecific, only tagging for promotion on more phenotypically broad panels.
---
Functional evidence (PMID: 39279645):

All patient fibroblasts showed decreased PTPMT1 protein expression. Cardiolipin content was decreased in one case but normal in another unrelated individual. Mitochondria in fibroblasts from 2 cases (distantly related) displayed fragmentation and abnormal shape - rescued using expression of WT PTPMT1.

A ptpmt1 knockout zebrafish model showed abnormalities in head and body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.
Possible mitochondrial disorder - nuclear genes v5.10 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Tag Q2_26_expert_review tag was added to gene: PTPMT1.
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Tag watchlist was removed from gene: PTPMT1.
Tag Q2_26_promote_green tag was added to gene: PTPMT1.
Tag Q2_26_NHS_review tag was added to gene: PTPMT1.
Possible mitochondrial disorder - nuclear genes v5.9 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Possible mitochondrial disorder - nuclear genes v5.9 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Classified gene: PTPMT1 as Amber List (moderate evidence)
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with the Genomics England Clinical Team (William Macken and Helen Brittain) it was decided that it may be possible to classify this gene as green given the reasonably extensive functional work (further outlined below); however, inclusion should first be reviewed by the GMS expert team. As the phenotype is nonspecific, only tagging for promotion on more phenotypically broad panels.
---
Functional evidence (PMID: 39279645):

All patient fibroblasts showed decreased PTPMT1 protein expression. Cardiolipin content was decreased in one case but normal in another unrelated individual. Mitochondria in fibroblasts from 2 cases (distantly related) displayed fragmentation and abnormal shape - rescued using expression of WT PTPMT1.

A ptpmt1 knockout zebrafish model showed abnormalities in head and body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.
Mitochondrial disorders v10.11 PTPMT1 Arina Puzriakova Gene: ptpmt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.45 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Intellectual disability v10.45 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Early onset or syndromic epilepsy v9.23 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Early onset or syndromic epilepsy v9.23 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Severe microcephaly v9.9 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Severe microcephaly v9.9 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Ataxia and cerebellar anomalies - narrow panel v9.10 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Ataxia and cerebellar anomalies - narrow panel v9.10 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Mitochondrial disorders v10.10 PTPMT1 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026
Mitochondrial disorders v10.10 PTPMT1 Arina Puzriakova Phenotypes for gene: PTPMT1 were changed from neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199
Endocrine neoplasia v3.8 GPR101 Arina Puzriakova Classified gene: GPR101 as Amber List (moderate evidence)
Endocrine neoplasia v3.8 GPR101 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple cases with germline variants causing syndromic overgrowth with pituitary macroadenoma or hyperplasia which is within the scope of this panel.
Endocrine neoplasia v3.8 GPR101 Arina Puzriakova Gene: gpr101 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.8 GPR101 Arina Puzriakova Classified gene: GPR101 as Amber List (moderate evidence)
Paediatric disorders - additional genes v8.8 GPR101 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - multiple cases with germline variants causing syndromic overgrowth which is within the scope of this panel.
Paediatric disorders - additional genes v8.8 GPR101 Arina Puzriakova Gene: gpr101 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.7 GPR101 Arina Puzriakova gene: GPR101 was added
gene: GPR101 was added to Paediatric disorders - additional genes. Sources: Literature
Q2_26_promote_green tags were added to gene: GPR101.
Mode of inheritance for gene: GPR101 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: GPR101 were set to 29389097; 25470569; 25806920; 26982009; 27245663; 27743704; 32958754
Phenotypes for gene: GPR101 were set to Pituitary adenoma 2, GH-secreting, OMIM:300943
Review for gene: GPR101 was set to GREEN
Added comment: Heterozygous or hemizygous germline variants or somatic duplications in GPR101 lead to X-linked pituitary gigantism/acrogigantism characterised by marked overgrowth in early childhood, often within the first months of life, due to excess of GH. Most patients present with concomitant hyperprolactinaemia. Histopathology shows pituitary hyperplasia or pituitary adenoma with or without associated hyperplasia. At least 30 individuals have been reported to date - mostly females harbouring germline variants, while males typically carry somatic mosaic variants although a small number of males with a germline duplication inherited from their affected mother have also been reported.
Sources: Literature
Endocrine neoplasia v3.7 GPR101 Arina Puzriakova gene: GPR101 was added
gene: GPR101 was added to Endocrine neoplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: GPR101.
Mode of inheritance for gene: GPR101 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: GPR101 were set to 29389097; 25470569; 25806920; 26982009; 27245663; 27743704; 32958754
Phenotypes for gene: GPR101 were set to Pituitary adenoma 2, GH-secreting, OMIM:300943
Review for gene: GPR101 was set to GREEN
Added comment: Heterozygous or hemizygous germline variants or somatic duplications in GPR101 lead to X-linked pituitary gigantism/acrogigantism characterised by marked overgrowth in early childhood, often within the first months of life, due to excess of GH. Most patients present with concomitant hyperprolactinaemia. Histopathology shows pituitary hyperplasia or pituitary adenoma with or without associated hyperplasia. At least 30 individuals have been reported to date - mostly females harbouring germline variants, while males typically carry somatic mosaic variants although a small number of males with a germline duplication inherited from their affected mother have also been reported.
Sources: Literature
Congenital fibrosis of the extraocular muscles v2.4 ZFHX4 Nicky Cronbach gene: ZFHX4 was added
gene: ZFHX4 was added to Congenital fibrosis of the extraocular muscles. Sources: Literature
Mode of inheritance for gene: ZFHX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFHX4 were set to PMID: 41524020; 11935336; 32962661
Phenotypes for gene: ZFHX4 were set to Isolated congenital ptosis
Penetrance for gene: ZFHX4 were set to unknown
Review for gene: ZFHX4 was set to GREEN
Added comment: Multiple unrelated cases of isolated congenital ptosis reported. Three unrelated Han-Chinese patients (PMID 41524020) and one Nepalese patient (32962661) with missense variants in ZFHX4, and one case (unspecified ethnicity) related to a translocation disrupting ZFHX4.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFH Ida Ertmanska changed review comment from: PMID: 36211394 Gouda et al., 2022
Egyptian cohort of 40 patients with LN, lupus nephritis (23) or PIGN, post-infectious glomerulonephritis (17), tested for genetic variants in CFH and CD46 genes. VUS CFH:p.F614S variant was found in 28 (70%) of patients: 17 (74%) of LN patients, and 11 (65%) of PIGN patients. 3 Pathogenic CFH mutations were detected in a heterozygous state in LN patients: c.514C>T (p.Q172*), c.2103G>A (p.W701*), and c.3288G>A (p.W1096*).

PMID: 35084692 Shears et al., 2022
Forty patients, median age 19 (range 3–62) years, were identified with terminal complement deficiencies. 2 White European patients had CFH variants and meningococcal infections and septicemia; 1 patient had non-meningococcal sepsis. Both were homozygous for CFH c.2T>C, p.Met1? variant (related?).

PMID: 32064578 Brodszki et al., 2020
"Complement deficiencies account for ~5% of PIDs." <30 patients reported with CFH variants according to the lit review.

PMID: 31440263 Sissy et al., 2019
13 patients reported with 7 different homozygous CFH variants and Factor H deficiency (primarily resulting in severe or multiple infections—mainly meningococcal infections—or severe autoimmune diseases). However, in this cohort, all 13 patients with CFH variants presented with kidney disease and no recurrent infections.

PMID: 14978182 Dragon-Durey et al., 2004
Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. No mention of recurring infections in these patients - authors pose that previously reported susceptibility to meningococcal disease is secondary to acquired C3 or C5-C9 deficiencies.

Functional:
PMID: 12091909 Pickering et al., 2002 - mouse Cfh knockout caused membranoproliferative glomerulonephritis, seen at 8 months old.

CFH is associated with AD,AR Complement factor H deficiency, OMIM:609814 and AD, AR {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400, among others (OMIM accessed 22nd Jun 2026). The association between CFH and semidominant atypical hemolytic-uremic syndrome is Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, July 2023); CFH-related AR C3 glomerulonephritis is also Definitive (Complement-Mediated Kidney Diseases GCEP, Feb 2024).; to: PMID: 36211394 Gouda et al., 2022
Egyptian cohort of 40 patients with LN, lupus nephritis (23) or PIGN, post-infectious glomerulonephritis (17), tested for genetic variants in CFH and CD46 genes. VUS CFH:p.F614S variant was found in 28 (70%) of patients: 17 (74%) of LN patients, and 11 (65%) of PIGN patients. 3 Pathogenic CFH mutations were detected in a heterozygous state in LN patients: c.514C>T (p.Q172*), c.2103G>A (p.W701*), and c.3288G>A (p.W1096*).

PMID: 35084692 Shears et al., 2022
Forty patients, median age 19 (range 3–62) years, were identified with terminal complement deficiencies. 2 White European patients had CFH variants and meningococcal infections and septicemia; 1 of these patients also had non-meningococcal sepsis. Both were homozygous for CFH c.2T>C, p.Met1? variant (related?).

PMID: 32064578 Brodszki et al., 2020
"Complement deficiencies account for ~5% of PIDs." <30 patients reported with CFH variants according to the lit review.

PMID: 31440263 Sissy et al., 2019
13 patients reported with 7 different homozygous CFH variants and Factor H deficiency (primarily resulting in severe or multiple infections—mainly meningococcal infections—or severe autoimmune diseases). However, in this cohort, all 13 patients with CFH variants presented with kidney disease and no recurrent infections.

PMID: 14978182 Dragon-Durey et al., 2004
Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. No mention of recurring infections in these patients - authors pose that previously reported susceptibility to meningococcal disease is secondary to acquired C3 or C5-C9 deficiencies.

Functional:
PMID: 12091909 Pickering et al., 2002 - mouse Cfh knockout caused membranoproliferative glomerulonephritis, seen at 8 months old.

CFH is associated with AD,AR Complement factor H deficiency, OMIM:609814 and AD, AR {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400, among others (OMIM accessed 22nd Jun 2026). The association between CFH and semidominant atypical hemolytic-uremic syndrome is Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, July 2023); CFH-related AR C3 glomerulonephritis is also Definitive (Complement-Mediated Kidney Diseases GCEP, Feb 2024).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFB Ida Ertmanska changed review comment from: PMID: 41663882 Bougeard et al., 2026
Report of a 14yo French girl with Neisseria meningitidis serogroup Y meningitis complicated by bacteremia and cerebral venous sinus thrombosis. She was found to be comp het for CFB: p.Gly396Arg and p.Gln713Arg.

PMID: 33165708 Gauthier et al., 2021
8yo male, Caucasian, with repeated pneumococcal infections: pneumococcal bacteriemia at 4 months, pneumococcal meningitis and bacteriemia at 11 months, empyema caused by S. pneumoniae at 8 years: pneumonia with septic shock and acute respiratory distress syndrome (intubated for 9 days + mechanical ventilation + 7 days of extracorporeal membrane oxygenation). Compound heterozygous for CFB variants c.1938dup, p.(Ile647Hisfs*6) and c.1186G>A, p.(Gly396Arg).

PMID: 24152280 Slade et al., 2018
32yo female, recurrent episodes of pneumococcal and meningococcal infections starting at age 2 yrs. She was compound heterozygous for CFB: c.766C>T, p.Gln256* (nonsense), c.1895_1898del, p.Phe632Cysfs*8 (frameshift). Factor B levels were undetectable in the patient.

PMCID: PMC3334074 Dehoorne et al., 2008
Report of a 16-y-old Caucasian girl, who presented with recurrent episodes of aseptic meningitis. She presented with a 2-week history of headache, vomiting, neck stiffness, facial palsy, equilibrium problems, diplopia, and low grade temperature. 4 months prior to admission she presented with a leucocytoclastic vasculitis. Biochemical testing showed very low levels of factor B (1mg/dl), but normal factors I and H. No genetic testing described.

CFB is associated with AR Complement factor B deficiency, MIM:615561 and AD {Hemolytic uremic syndrome, atypical, susceptibility to, 4}, MIM:612924 in OMIM (accessed 22nd Jun 2026).
The association between CFB and AD C3 glomerulonephritis was classified as Limited (Nov 2024), and CFB-related AD atypical hemolytic-uremic syndrome with B factor anomaly was classified as Moderate (July 2023) by the ClinGen Complement-Mediated Kidney Diseases GCEP.; to: PMID: 41663882 Bougeard et al., 2026
Report of a 14yo French girl with Neisseria meningitiis serogroup Y complicated by bacteremia and cerebral venous sinus thrombosis. She was found to be comp het for CFB: p.Gly396Arg and p.Gln713Arg.

PMID: 33165708 Gauthier et al., 2021
8yo male, Caucasian, with repeated pneumococcal infections: pneumococcal bacteriemia at 4 months, pneumococcal meningitis and bacteriemia at 11 months, empyema caused by S. pneumoniae at 8 years: pneumonia with septic shock and acute respiratory distress syndrome (intubated for 9 days + mechanical ventilation + 7 days of extracorporeal membrane oxygenation). Compound heterozygous for CFB variants c.1938dup, p.(Ile647Hisfs*6) and c.1186G>A, p.(Gly396Arg).

PMID: 24152280 Slade et al., 2018
32yo female, recurrent episodes of pneumococcal and meningococcal infections starting at age 2 yrs. She was compound heterozygous for CFB: c.766C>T, p.Gln256* (nonsense), c.1895_1898del, p.Phe632Cysfs*8 (frameshift). Factor B levels were undetectable in the patient.

PMCID: PMC3334074 Dehoorne et al., 2008
Report of a 16-y-old Caucasian girl, who presented with recurrent episodes of aseptic meningitis. She presented with a 2-week history of headache, vomiting, neck stiffness, facial palsy, equilibrium problems, diplopia, and low grade temperature. 4 months prior to admission she presented with a leucocytoclastic vasculitis. Biochemical testing showed very low levels of factor B (1mg/dl), but normal factors I and H. No genetic testing described.

CFB is associated with AR Complement factor B deficiency, MIM:615561 and AD {Hemolytic uremic syndrome, atypical, susceptibility to, 4}, MIM:612924 in OMIM (accessed 22nd Jun 2026).
The association between CFB and AD C3 glomerulonephritis was classified as Limited (Nov 2024), and CFB-related AD atypical hemolytic-uremic syndrome with B factor anomaly was classified as Moderate (July 2023) by the ClinGen Complement-Mediated Kidney Diseases GCEP.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFH Ida Ertmanska Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFH Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have recurrent (meningococcal) infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene is tagged for demotion from Green to Amber, with expert review also requested.; to: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have recurrent (meningococcal) infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene will be tagged for demotion from Green to Amber, with expert review also requested.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CFH Ida Ertmanska Tag Q2_26_expert_review was removed from gene: CFH.
Tag Q2_26_demote_amber was removed from gene: CFH.
Fetal anomalies v7.24 VCP Arina Puzriakova Classified gene: VCP as Amber List (moderate evidence)
Fetal anomalies v7.24 VCP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated individuals with Adams-Oliver syndrome due to heterozygous hypermorphic variants in the NTD domain of VCP.
Fetal anomalies v7.24 VCP Arina Puzriakova Gene: vcp has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.22 VCP Arina Puzriakova Classified gene: VCP as Amber List (moderate evidence)
Skeletal dysplasia v9.22 VCP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated individuals with Adams-Oliver syndrome due to heterozygous hypermorphic variants in the NTD domain of VCP.
Skeletal dysplasia v9.22 VCP Arina Puzriakova Gene: vcp has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v4.14 VCP Arina Puzriakova Classified gene: VCP as Amber List (moderate evidence)
Pulmonary arterial hypertension v4.14 VCP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated individuals with Adams-Oliver syndrome, of which 6 had pulmonary hypertension, due to heterozygous hypermorphic variants in the NTD domain of VCP.
Pulmonary arterial hypertension v4.14 VCP Arina Puzriakova Gene: vcp has been classified as Amber List (Moderate Evidence).
Limb disorders v8.16 VCP Arina Puzriakova Classified gene: VCP as Amber List (moderate evidence)
Limb disorders v8.16 VCP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 7 unrelated individuals with Adams-Oliver syndrome due to heterozygous hypermorphic variants in the NTD domain of VCP.
Limb disorders v8.16 VCP Arina Puzriakova Gene: vcp has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CD46 Ida Ertmanska edited their review of gene: CD46: Changed rating: AMBER; Changed publications to: 14566051, 16621965, 16762990, 29644059, 33238263, 40983966; Changed phenotypes to: {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 CD46 Ida Ertmanska changed review comment from: PMID: 33238263 Bamhraz et al., 2020
Saudi Arabian aHUS cohort.
Patient 1 homozygous for CD46: c.736T>A (p.Phe246Ile) variant, as well as het for CFI c.540A>G (p.Glu180Glu) - both labelled VUS. Disease onset at 10yrs, complete recovery after eculizumab treatment.
Patient 5 - homozygous for CD46: c.769 C>A (p.Cys 256*) - LP, as well as heterozygous for CFI c.803 C>T (p.Ser268Leu) variant (LB). Disease onset at 2.5yrs, developed into ESRD and required a post-kidney transplant.
Patient 7 - homozygous for CD46: c.350-351dup AC (p.Glu11ThfsX17) - LP. Disease onset at 21 months. Patient responded to plasma therapy leading to full recovery.

PMID: 29644059 Khandelwal et al., 2018
Cohort of Indian children with aHUS.
Sibling pairs 2–3 and 7–8 with familial disease showed a homozygous c.286 + 2T > G splice-site mutation; in both families, the parents were consanguineous. Patient 9 had a homozygous c.104G > A, p.Cys35Tyr; his affected sibling had died before genetic evaluation. 3 unrelated families total.; to: BIALLELIC CASES:
PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced. Other modifier mutations may affect penetrance here.

PMID: 33238263 Bamhraz et al., 2020
Saudi Arabian aHUS cohort.
Patient 1 homozygous for CD46: c.736T>A (p.Phe246Ile) variant, as well as het for CFI c.540A>G (p.Glu180Glu) - both labelled VUS. Disease onset at 10yrs, complete recovery after eculizumab treatment.
Patient 5 - homozygous for CD46: c.769 C>A (p.Cys 256*) - LP, as well as heterozygous for CFI c.803 C>T (p.Ser268Leu) variant (LB). Disease onset at 2.5yrs, developed into ESRD and required a post-kidney transplant.
Patient 7 - homozygous for CD46: c.350-351dup AC (p.Glu11ThfsX17) - LP. Disease onset at 21 months. Patient responded to plasma therapy leading to full recovery.

PMID: 29644059 Khandelwal et al., 2018
Cohort of Indian children with aHUS.
Sibling pairs 2–3 and 7–8 with familial disease showed a homozygous c.286 + 2T > G splice-site mutation; in both families, the parents were consanguineous. Patient 9 had a homozygous c.104G > A, p.Cys35Tyr; his affected sibling had died before genetic evaluation. 3 unrelated families total.

PMID: 16762990 Fremeaux-Bacchi et al., 2006
3 homozygous aHUS patients (onset at 2, 5, and 27yrs).
Patient 1 - born with Pierre Robin sequence, presented with common variable immunodeficiency. Developed aHUS at 27yrs. Homozygous for CD46 R25X. MFI on granulocytes for CD46 expression was 0.
Patient 2 was homozygous for CD46 Y214X (no CD46 expression on granulocytes; Patient 3 homozygous for IVS2+2T>G - CD46 MFI level was 46 (normal range 600-1400). No mention of immunodeficiency in Patients 2 & 3.

PMID: 16621965 Caprioli et al., 2006
Family 099 - Sardinian origin, 2 individuals homozygous for CD46 IVS1-1G > C, and 1 heterozygous affected member (4 het carriers unaffected). The homozygous sibs developed aHUS early (before age 4 yrs); adult onset seen in heterozygous family members.
Family 024 - 2 comp het sibs CD46 variants c.218C>T, p.R25Stop & c.147G>A, p.C1Y - showed almost no MCP staining by FACS. Parents were carriers of 1 mutation each, unaffected.

PMID: 14566051 Richards et al., 2003
Family 3 - recessive aHUS, CD46 c.822T>C, p.Ser206Pro. Same mutation caused aHUS in Family 2 in a heterozygous state. Demonstrated that het patients had protein expression reduced by 50%, and it was absent in homozygotes.
Pulmonary arterial hypertension v4.13 VCP Arina Puzriakova gene: VCP was added
gene: VCP was added to Pulmonary arterial hypertension. Sources: Literature
Q2_26_promote_green tags were added to gene: VCP.
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 41979051
Phenotypes for gene: VCP were set to Adams-Oliver syndrome, MONDO:0007034
Mode of pathogenicity for gene: VCP 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: VCP was set to GREEN
Added comment: Lehman et al 2026 (PMID: 41979051) report 7 unrelated families with Adams-Oliver syndrome characterised by aplasia cutis congenita and terminal limb reduction defects. Members of three families displayed features of multisystem proteinopathy, previously associated with this gene, including a parent (myopathy, lytic bone lesions and/or neuropathy in F1 and 2) or grandparent (frontotemporal dementia in F4). Pulmonary hypertension was found in 6/7 families.

Heterozygous rare missense variants in the VCP gene were identified by WGS or WES (4 de novo, 2 inherited and 1 presumed inherited). Variants clustered in the N-terminal domain (NTD), and the same amino acid residue, p.Arg89, was altered in 4/7 families. Variants were shown to exert a GoF effect, leading to overactive ATP hydrolysis and caused NTD hyperflexibility with loss of interdomain coupling.
Sources: Literature
Fetal anomalies v7.23 VCP Arina Puzriakova gene: VCP was added
gene: VCP was added to Fetal anomalies. Sources: Literature
Q2_26_promote_green tags were added to gene: VCP.
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 41979051
Phenotypes for gene: VCP were set to Adams-Oliver syndrome, MONDO:0007034
Mode of pathogenicity for gene: VCP 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: VCP was set to GREEN
Added comment: Lehman et al 2026 (PMID: 41979051) report 7 unrelated families with Adams-Oliver syndrome characterised by aplasia cutis congenita and terminal limb reduction defects. Members of three families displayed features of multisystem proteinopathy, previously associated with this gene, including a parent (myopathy, lytic bone lesions and/or neuropathy in F1 and 2) or grandparent (frontotemporal dementia in F4). Pulmonary hypertension was found in 6/7 families.

Heterozygous rare missense variants in the VCP gene were identified by WGS or WES (4 de novo, 2 inherited and 1 presumed inherited). Variants clustered in the N-terminal domain (NTD), and the same amino acid residue, p.Arg89, was altered in 4/7 families. Variants were shown to exert a GoF effect, leading to overactive ATP hydrolysis and caused NTD hyperflexibility with loss of interdomain coupling.
Sources: Literature
Skeletal dysplasia v9.21 VCP Arina Puzriakova gene: VCP was added
gene: VCP was added to Skeletal dysplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: VCP.
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 41979051
Phenotypes for gene: VCP were set to Adams-Oliver syndrome, MONDO:0007034
Mode of pathogenicity for gene: VCP 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: VCP was set to GREEN
Added comment: Lehman et al 2026 (PMID: 41979051) report 7 unrelated families with Adams-Oliver syndrome characterised by aplasia cutis congenita and terminal limb reduction defects. Members of three families displayed features of multisystem proteinopathy, previously associated with this gene, including a parent (myopathy, lytic bone lesions and/or neuropathy in F1 and 2) or grandparent (frontotemporal dementia in F4). Pulmonary hypertension was found in 6/7 families.

Heterozygous rare missense variants in the VCP gene were identified by WGS or WES (4 de novo, 2 inherited and 1 presumed inherited). Variants clustered in the N-terminal domain (NTD), and the same amino acid residue, p.Arg89, was altered in 4/7 families. Variants were shown to exert a GoF effect, leading to overactive ATP hydrolysis and caused NTD hyperflexibility with loss of interdomain coupling.
Sources: Literature
Limb disorders v8.15 VCP Arina Puzriakova gene: VCP was added
gene: VCP was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: VCP.
Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCP were set to 41979051
Phenotypes for gene: VCP were set to Adams-Oliver syndrome, MONDO:0007034
Mode of pathogenicity for gene: VCP 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: VCP was set to GREEN
Added comment: Lehman et al 2026 (PMID: 41979051) report 7 unrelated families with Adams-Oliver syndrome characterised by aplasia cutis congenita and terminal limb reduction defects. Members of three families displayed features of multisystem proteinopathy, previously associated with this gene, including a parent (myopathy, lytic bone lesions and/or neuropathy in F1 and 2) or grandparent (frontotemporal dementia in F4). Pulmonary hypertension was found in 6/7 families.

Heterozygous rare missense variants in the VCP gene were identified by WGS or WES (4 de novo, 2 inherited and 1 presumed inherited). Variants clustered in the N-terminal domain (NTD), and the same amino acid residue, p.Arg89, was altered in 4/7 families. Variants were shown to exert a GoF effect, leading to overactive ATP hydrolysis and caused NTD hyperflexibility with loss of interdomain coupling.
Sources: Literature
Fetal anomalies v7.22 NPR2 Ida Ertmanska changed review comment from: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).

Consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as heterozygous individuals also present with skeletal features, limb disorders.; to: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).

Brachydactyly is a consistent feature in recessive NPR2-related skeletal dysplasia (Acromesomelic dysplasia 1, Maroteaux type). Heterozygous individuals also present with skeletal features, limb disorders. Hence, consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Fetal anomalies v7.22 NPR2 Ida Ertmanska changed review comment from: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals (> 2 years old and height <-3SD).

Consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as heterozygous individuals also present with skeletal features, limb disorders.; to: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).

Consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as heterozygous individuals also present with skeletal features, limb disorders.
Skeletal dysplasia v9.20 GHR Ida Ertmanska Tag treatable tag was added to gene: GHR.
Monogenic short stature v2.8 GHR Ida Ertmanska Tag treatable tag was added to gene: GHR.
Skeletal dysplasia v9.20 GHR Ida Ertmanska commented on gene: GHR: NHS Clinical Commissioning Policy: Mecasermin for treatment of growth failure (April 2013): "The NHS Commissioning Board (NHS CB) will commission mecasermin for children and adolescents with growth failure due to severe primary insulin-like growth factor1 deficiency (SPIGFD)" - treatable tag has been added.
Pituitary hormone deficiency v4.10 GHR Ida Ertmanska Tag treatable tag was added to gene: GHR.
Pituitary hormone deficiency v4.10 GHR Ida Ertmanska commented on gene: GHR: NHS Clinical Commissioning Policy: Mecasermin for treatment of growth failure (April 2013): "The NHS Commissioning Board (NHS CB) will commission mecasermin for children and adolescents with growth failure due to severe primary insulin-like growth factor1 deficiency (SPIGFD)" - treatable tag has been added.
Pituitary hormone deficiency v4.10 GHR Ida Ertmanska commented on gene: GHR: NHS Clinical Commissioning Policy: Mecasermin for treatment of growth failure (April 2013): "The NHS Commissioning Board (NHS CB) will commission mecasermin for children and adolescents with growth failure due to severe primary insulin-like growth factor1 deficiency (SPIGFD)" - treatable tag has been added.
Monogenic short stature v2.8 GHR Ida Ertmanska commented on gene: GHR: NHS Clinical Commissioning Policy: Mecasermin for treatment of growth failure (April 2013): "The NHS Commissioning Board (NHS CB) will commission mecasermin for children and adolescents with growth failure due to severe primary insulin-like growth factor1 deficiency (SPIGFD)" - treatable tag has been added.
Hereditary neuropathy v1.510 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Charcot-Marie-Tooth disease, type 2Y; Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia; Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 to Charcot-Marie-Tooth disease, type 2Y, OMIM:616687
Amyotrophic lateral sclerosis/motor neuron disease v1.75 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954; Amyotrophic Lateral Sclerosis, Dominant; familial amyotrophic lateral sclerosis (ALS14) to Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, OMIM:613954
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.15 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 167320 to Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, OMIM:167320
Arthrogryposis v10.13 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954 Inclusion body myopathy,Paget disease and frontotemporal dementia 1, 167320 ; Inclusion Body Myopathy, Dominant; Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia to nclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, OMIM:167320
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.85 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia, 613954 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 6, OMIM:613954
Distal myopathies v7.5 VCP Arina Puzriakova Phenotypes for gene: VCP were changed from Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, 167320 to Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, OMIM:167320
Monogenic hearing loss v6.25 COL9A3 Ida Ertmanska Phenotypes for gene: COL9A3 were changed from Stickler syndrome, MONDO:0019354 to Stickler syndrome, MONDO:0019354; Stickler syndrome, type VI, OMIM:620022
Stickler syndrome v4.11 COL9A3 Ida Ertmanska Phenotypes for gene: COL9A3 were changed from Stickler syndrome, MONDO:0019354 to Stickler syndrome, MONDO:0019354; Stickler syndrome, type VI, OMIM:620022
Stickler syndrome v4.10 GZF1 Ida Ertmanska Phenotypes for gene: GZF1 were changed from Larsen syndrome, MONDO:0007875 to Larsen syndrome, MONDO:0007875; JOINT LAXITY, SHORT STATURE, AND MYOPIA, OMIM:617662
Intellectual disability v10.44 UBR5 Ida Ertmanska Phenotypes for gene: UBR5 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Neurodevelopmental disorder with speech delay and behavioral abnormalities, OMIM:621372
Early onset or syndromic epilepsy v9.22 UBR5 Ida Ertmanska Phenotypes for gene: UBR5 were changed from complex neurodevelopmental disorder, MONDO:0100038 to Neurodevelopmental disorder with speech delay and behavioral abnormalities, OMIM:621372
Ataxia and cerebellar anomalies - narrow panel v9.9 TTBK2 Ida Ertmanska Phenotypes for gene: TTBK2 were changed from Spinocerebellar ataxia 11 to Spinocerebellar ataxia 11, OMIM:604432; spinocerebellar ataxia type 11, MONDO:0011464
Likely inborn error of metabolism v9.17 STS Ida Ertmanska Phenotypes for gene: STS were changed from X-linked ichthyosis (Other disorders in the metabolism of sterols); Autosomal recessive congenital ichthyosis to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269
Corneal dystrophy v4.11 STS Ida Ertmanska Phenotypes for gene: STS were changed from Ichthyosis, X-linked to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269
Palmoplantar keratodermas v4.16 STS Ida Ertmanska Phenotypes for gene: STS were changed from X linked ichthyosis to Ichthyosis, X-linked, OMIM:308100; ichthyosis, MONDO:0019269
Intellectual disability v10.43 STAG2 Ida Ertmanska Phenotypes for gene: STAG2 were changed from STAG2-related developmental delay with microcephaly and congenital anomalies; STAG2-related X-linked Intellectual Deficiency; cohesinopathy; Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology to Holoprosencephaly 13, X-linked, OMIM:301043; Mullegama-Klein-Martinez syndrome, OMIM:301022
Respiratory ciliopathies including non-CF bronchiectasis v5.3 SPEF2 Ida Ertmanska Phenotypes for gene: SPEF2 were changed from Spermatogenic failure 43, OMIM:618751, MONDO:0032898; Primary ciliary dyskinesia-like phenotype to Spermatogenic failure 43, OMIM:618751; Primary ciliary dyskinesia-like phenotype
Hereditary neuropathy or pain disorder v8.9 RCC1 Ida Ertmanska Phenotypes for gene: RCC1 were changed from Severe, acute-onset axonal neuropathy following infection to Infection-induced acute-onset axonal neuropathy, OMIM:621333; infection-induced acute-onset axonal neuropathy, MONDO:0979881
Pigmentary skin disorders v5.11 RAB27A Ida Ertmanska Phenotypes for gene: RAB27A were changed from GS2; GRISCELLI SYNDROME, TYPE 2; Griscelli syndrome to Griscelli syndrome, type 2, OMIM:607624; Griscelli syndrome type 2, MONDO:0011872
Adult onset hereditary spastic paraplegia v6.12 PSEN1 Ida Ertmanska Phenotypes for gene: PSEN1 were changed from Alzheimer disease, type 3, with spastic paraparesis, apraxia and unusual plaques; Alzheimer disease, type 3, with spastic paraparesis and apraxia; Alzheimer disease, type 3, with spastic paraparesis and unusual plaques to Alzheimer disease, type 3, with or without spastic paraparesis, OMIM:607822
Retinal disorders v9.10 PLA2G5 Ida Ertmanska Phenotypes for gene: PLA2G5 were changed from Eye Disorders to [Fleck retina, familial benign], OMIM:228980
Intellectual disability v10.42 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904
Likely inborn error of metabolism v9.16 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, OMIM:618135; muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, MONDO:0029135
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.14 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 8, 614830; limb girdle muscular dystrophy to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, OMIM:618135; muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, MONDO:0029135
Ataxia and cerebellar anomalies - narrow panel v9.8 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies type to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904
Arthrogryposis v10.12 POMGNT2 Ida Ertmanska Phenotypes for gene: POMGNT2 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies type; Walker-Warburg syndrome to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8, OMIM:614830; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8, MONDO:0013904; Muscular dystrophy-dystroglycanopathy (limb-girdle) type C, 8, OMIM:618135; muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, MONDO:0029135
Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 PIK3CG Ida Ertmanska Phenotypes for gene: PIK3CG were changed from Immunodeficiency 97 with autoinflammation, OMIM:619802 to Immunodeficiency 97 with autoinflammation, OMIM:619802; immunodeficiency 97 with autoinflammation, MONDO:0030717
Primary immunodeficiency or monogenic inflammatory bowel disease v9.17 PIK3CG Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.17 PIK3CG Ida Ertmanska Phenotypes for gene: PIK3CG were changed from Immune dysregulation; HLH-like; childhood-onset antibody defects; cytopenias; T lymphocytic pneumonitis and colitis to Immunodeficiency 97 with autoinflammation, OMIM:619802
Vascular skin disorders v2.7 PIK3CA Ida Ertmanska Phenotypes for gene: PIK3CA were changed from PIK3CA-related overgrowth syndromes; Vascular malformation, MONDO:0024291 to PIK3CA-related overgrowth syndromes; Vascular malformation, MONDO:0024291; CLAPO syndrome, somatic, OMIM:613089; Nevus, epidermal, somatic mosaic, OMIM:162900; CLOVE syndrome, somatic, OMIM:612918; Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501
Mosaic skin disorders - deep sequencing v3.34 PIK3CA Ida Ertmanska Phenotypes for gene: PIK3CA were changed from PIK3CA-related overgrowth syndromes; Vascular malformations to CLAPO syndrome, somatic, OMIM:613089; Nevus, epidermal, somatic mosaic, OMIM:162900; CLOVE syndrome, somatic, OMIM:612918
Malformations of cortical development v8.6 PIK3CA Ida Ertmanska Phenotypes for gene: PIK3CA were changed from Polymicrogyria, hemimegalencephaly, macrocephaly to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501; Cerebral cavernous malformations 4, somatic, OMIM:619538
Pigmentary skin disorders v5.10 PIK3CA Ida Ertmanska Phenotypes for gene: PIK3CA were changed from MCAP; PIK3CA-related overgrowth syndromes; MEGALENCEPHALY-CAPILLARY MALFORMATION-POLYMICROGYRIA SYNDROME; Vascular malformations to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, OMIM:602501
Intellectual disability v10.41 TMEM63B Achchuthan Shanmugasundram Phenotypes for gene: TMEM63B were changed from Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275 to Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder; lung disorder, MONDO:0005275
Childhood onset dystonia, chorea or related movement disorder v8.5 PDYN Ida Ertmanska Phenotypes for gene: PDYN were changed from Spinocerebellar ataxia 23, 610245 to Spinocerebellar ataxia 23, OMIM:610245; spinocerebellar ataxia type 23, MONDO:0012449
Hereditary neuropathy or pain disorder v8.8 PDYN Ida Ertmanska Phenotypes for gene: PDYN were changed from Spinocerebellar ataxia 23, 610245; Cerebellar ataxia, sensory-motor axonal neuropathy to Spinocerebellar ataxia 23, OMIM:610245; spinocerebellar ataxia type 23, MONDO:0012449
Ataxia and cerebellar anomalies - narrow panel v9.7 PDYN Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Ataxia and cerebellar anomalies - narrow panel v9.7 PDYN Ida Ertmanska Phenotypes for gene: PDYN were changed from Spinocerebellar ataxia 23 to Spinocerebellar ataxia 23, OMIM:610245; spinocerebellar ataxia type 23, MONDO:0012449
Childhood interstitial lung disease v1.6 TMEM63B Achchuthan Shanmugasundram Phenotypes for gene: TMEM63B were changed from autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275 to autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder; lung disorder, MONDO:0005275
Congenital myopathy v7.77 TUBA4A Achchuthan Shanmugasundram changed review comment from: PMID:38413182 (2024) reported the identification of a recurrent novel heterozygous de novo variant (c.679C>T/ p.Leu227Phe) in the TUBA4A gene in two unrelated Chinese patients with sporadic congenital myopathy (14-year-old and 6-year-old females). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F variant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

PMID:41678358 (2026) reported a multi-centre study in which the authors identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease, while probands from the remaining two families presented with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation.

Four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. The disease onset ranged from congenital to late adulthood.

Of the three families with homozygous variants, the disease onset/ first clinical examination was only after 10 years in two (although motor delay reported in one family) and the third was 70-year-old patient also with a VUS variant in FLNC gene.

This gene has been associated only with AD congenital myopathy in OMIM (MIM #621225) and the record was last accessed 09 June 2026.; to: PMID:38413182 (2024) reported the identification of a recurrent novel heterozygous de novo variant (c.679C>T/ p.Leu227Phe) in the TUBA4A gene in two unrelated Chinese patients with sporadic congenital myopathy (14-year-old and 6-year-old females). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F variant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

PMID:41678358 (2026) reported a multi-centre study in which the authors identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease, while probands from the remaining two families presented with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation.

Four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. The disease onset ranged from congenital to late adulthood.

Of the three families with homozygous variants, the disease onset/ first clinical examination was only after 10 years in two (although motor delay reported in one family) and the third was 60-year-old patient with a VUS variant in FLNC gene, which has since been reported as LB in ClinVar.

This gene has been associated only with AD congenital myopathy in OMIM (MIM #621225) and the record was last accessed 09 June 2026.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.13 TUBA4A Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: TUBA4A.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.13 TUBA4A Achchuthan Shanmugasundram Classified gene: TUBA4A as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.13 TUBA4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There are several unrelated families reported with monoallelic TUBA4A variants and three unrelated families with biallelic TUBA4A variants. Hence, this gene can be considered for promotion to green rating with 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' MOI in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.13 TUBA4A Achchuthan Shanmugasundram Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.12 TUBA4A Achchuthan Shanmugasundram gene: TUBA4A was added
gene: TUBA4A was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Mode of inheritance for gene: TUBA4A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TUBA4A were set to 38413182; 41678358
Phenotypes for gene: TUBA4A were set to Congenital myopathy 26, OMIM:621225; congenital myopathy 26, MONDO:0979229
Review for gene: TUBA4A was set to GREEN
Added comment: PMID:38413182 (2024) reported the identification of a recurrent novel heterozygous de novo variant (c.679C>T/ p.Leu227Phe) in the TUBA4A gene in two unrelated Chinese patients with sporadic congenital myopathy (14-year-old and 6-year-old females). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F variant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

PMID:41678358 (2026) reported a multi-centre study in which the authors identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease, while probands from the remaining two families presented with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation.

Four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. The disease onset ranged from congenital to late adulthood. Three families with heterozygous variants and one with homozygous variant presented with myofibrillar disorganisation.

The following are details of the three patients with biallelic variants:
- Patient 26 (homozygous for c. 34G>A/ p.Ala12Thr) - myofibrillar myopathy with prominent axial muscle weakness, late-onset ataxia with cerebellar atrophy, nemaline bodies, proteinopathy. Age of onset at 60 years. The patient was also identified with a VUS variant in FLCN gene, which has since been reported as LB in ClinVar.
- Patient 21 (homozygous for c.722C>T/ p.Ser241Phe) - phenotype of myopathy / myo-tubulinopathy with fatigability and severe distal and proximal upper and lower limb weakness. Age of onset at 12 years.
- Patients 22/23 (siblings homozygous for c.1061G>A/ p.Gly354Asp) - phenotype listed as myopathy / myo-tubulinopathy with fatigability and generalised symmetrical weakness (distal and proximal). Age of onset from first year.

This gene has been associated only with AD congenital myopathy in OMIM (MIM #621225) and the record was last accessed 25 June 2026.
Sources: Literature
Childhood interstitial lung disease v1.5 TMEM63B Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, doi:10.1016/j.bdcasr.2024.100043. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature
Intellectual disability v10.40 TMEM63B Eleanor Williams Phenotypes for gene: TMEM63B were changed from Developmental and epileptic encephalopathy 118, OMIM:621250 to Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275
Intellectual disability v10.39 TMEM63B Eleanor Williams Publications for gene: TMEM63B were set to 37421948; 42259295
Intellectual disability v10.38 TMEM63B Eleanor Williams Publications for gene: TMEM63B were set to 37421948
Intellectual disability v10.37 TMEM63B Eleanor Williams Added comment: Comment on mode of inheritance: There are sufficient biallelic cases with loss of function variants and phenotype that includes moderate-severe developmental delay as well as lung disease to change the mode of inheritance to BOTH monoallelic and biallelic, autosomal or pseudoautosomal subject to GMS review.
Intellectual disability v10.37 TMEM63B Eleanor Williams Mode of inheritance for gene: TMEM63B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v10.36 TMEM63B Eleanor Williams Tag Q2_26_MOI tag was added to gene: TMEM63B.
Intellectual disability v10.36 TMEM63B Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss.

Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants.

In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals.; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed.

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss.

Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals.
Intellectual disability v10.36 TMEM63B Eleanor Williams Deleted their comment
Intellectual disability v10.36 TMEM63B Eleanor Williams commented on gene: TMEM63B: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss.

Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants.

In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals.
Intellectual disability v10.36 TMEM63B Eleanor Williams reviewed gene: TMEM63B: Rating: GREEN; Mode of pathogenicity: None; Publications: 42259295; Phenotypes: autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,, lung disorder, MONDO:0005275; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood interstitial lung disease v1.5 TMEM63B Eleanor Williams Phenotypes for gene: TMEM63B were changed from autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder to autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275
Childhood interstitial lung disease v1.4 TMEM63B Eleanor Williams Classified gene: TMEM63B as Amber List (moderate evidence)
Childhood interstitial lung disease v1.4 TMEM63B Eleanor Williams Added comment: Comment on list classification: Rating amber but with a recommendation for green rating following GMS review. There are 4 families with biallelic loss of function variants in this gene and a relevant phenotype.
Childhood interstitial lung disease v1.4 TMEM63B Eleanor Williams Gene: tmem63b has been classified as Amber List (Moderate Evidence).
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic pLoF variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature
Intellectual disability v10.36 KCNB1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Intellectual disability v10.36 KCNB1 Ida Ertmanska Phenotypes for gene: KCNB1 were changed from EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 26 to Developmental and epileptic encephalopathy 26, OMIM:616056; developmental and epileptic encephalopathy, 26, MONDO:0014477
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams changed review comment from: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic pLoF variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature; to: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic pLoF variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature
Early onset or syndromic epilepsy v9.21 KCNB1 Ida Ertmanska Publications for gene: KCNB1 were set to Torkamani et al (2014) Ann. Neurol. 76: 529-540, 2014
Early onset or syndromic epilepsy v9.20 KCNB1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Early onset or syndromic epilepsy v9.20 KCNB1 Ida Ertmanska Phenotypes for gene: KCNB1 were changed from Epileptic encephalopathy, early infantile, 26 to Developmental and epileptic encephalopathy 26, OMIM:616056; developmental and epileptic encephalopathy, 26, MONDO:0014477
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams Tag Q2_26_promote_green tag was added to gene: TMEM63B.
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams edited their review of gene: TMEM63B: Changed rating: GREEN
Childhood interstitial lung disease v1.3 TMEM63B Eleanor Williams gene: TMEM63B was added
gene: TMEM63B was added to Childhood interstitial lung disease. Sources: Literature
Mode of inheritance for gene: TMEM63B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63B were set to 42259295
Phenotypes for gene: TMEM63B were set to autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder
Review for gene: TMEM63B was set to AMBER
Added comment: Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250) with a gain-of-function mechanism proposed. Variants reported are either missense or an in-frame deletion. The main phenotypic features are severe early-onset developmental and epileptic encephalopathy, intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes (PMID: 37421948, https://www.sciencedirect.com/science/article/pii/S2950221724000394. Hearing loss is reported in mouse TMEM63B knockouts PMID: 32375046).

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss. Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic pLoF variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD.
Sources: Literature
Intellectual disability v10.35 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Intellectual disability v10.35 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699; neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v9.19 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Early onset or syndromic epilepsy v9.19 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027 to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027; Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Fetal anomalies v7.22 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Fetal anomalies v7.22 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Childhood onset hereditary spastic paraplegia v9.4 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIm phenotype updated.
Childhood onset hereditary spastic paraplegia v9.4 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental disorder, MONDO:0700092; Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Severe microcephaly v9.8 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Severe microcephaly v9.8 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149 to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149; Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Ataxia and cerebellar anomalies - narrow panel v9.6 INPP4A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated on 25th Jun 2026.
Ataxia and cerebellar anomalies - narrow panel v9.6 INPP4A Ida Ertmanska Phenotypes for gene: INPP4A were changed from neurodevelopmental disorder, MONDO:0700092; Cerebellar hypoplasia, HP:0001321 to Neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, OMIM:621354; neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, MONDO:0980699
Bleeding and platelet disorders v4.16 IKZF5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Bleeding and platelet disorders v4.16 IKZF5 Ida Ertmanska Phenotypes for gene: IKZF5 were changed from Thrombocytopenia (HP:0001873), Reduced platelet alpha granules (HP:0012528). to Thrombocytopenia, autosomal dominant, 7, OMIM:619130
Intellectual disability v10.34 ELFN1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Intellectual disability v10.34 ELFN1 Ida Ertmanska Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder, MONDO:0700092; Dursun-Ozgul neurodevelopmental syndrome, OMIM:621344
Early onset or syndromic epilepsy v9.18 ELFN1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Early onset or syndromic epilepsy v9.18 ELFN1 Ida Ertmanska Phenotypes for gene: ELFN1 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder, MONDO:0700092; Dursun-Ozgul neurodevelopmental syndrome, OMIM:621344
Malformations of cortical development v8.5 DPYSL5 Ida Ertmanska commented on gene: DPYSL5
Intellectual disability v10.33 DPYSL5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Intellectual disability v10.33 DPYSL5 Ida Ertmanska Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, OMIM:619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Malformations of cortical development v8.5 DPYSL5 Ida Ertmanska Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, OMIM:619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Ataxia and cerebellar anomalies - narrow panel v9.5 DPYSL5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Ataxia and cerebellar anomalies - narrow panel v9.5 DPYSL5 Ida Ertmanska Phenotypes for gene: DPYSL5 were changed from Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities to Ritscher-Schinzel syndrome 4, OMIM:619435; Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Palmoplantar keratodermas v4.15 CYP4F22 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Palmoplantar keratodermas v4.15 CYP4F22 Ida Ertmanska Phenotypes for gene: CYP4F22 were changed from Autosomal recessive congenital ichthyosis to Ichthyosis, congenital, autosomal recessive 5, OMIM:604777
Early onset or syndromic epilepsy v9.17 SF3B1 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with 13 individuals reported to have seizures. Based on available evidence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with 13 individuals reported to have seizures. Based on available evidence, this gene can be promoted to Green at the next update.
Clefting v7.7 SF3B1 Ida Ertmanska changed review comment from: Comment on list classification: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with clefting / high-arched palate seen in 12/26 patients. Based on available evidence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with clefting / high-arched palate seen in 12/26 patients. Based on available evidence, this gene can be promoted to Green at the next update.
Likely inborn error of metabolism v9.15 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Mitochondrial disorder with complex IV deficiency v5.4 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Hereditary neuropathy or pain disorder v8.7 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Hereditary neuropathy or pain disorder v8.7 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Mitochondrial disorders v10.9 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Mitochondrial disorders v10.9 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Possible mitochondrial disorder - nuclear genes v5.8 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Possible mitochondrial disorder - nuclear genes v5.8 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; ?Mitochondrial complex IV deficiency, nuclear type 25, OMIM:621487; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Likely inborn error of metabolism v9.14 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Likely inborn error of metabolism v9.14 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Mitochondrial disorder with complex IV deficiency v5.3 COX18 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Mitochondrial disorder with complex IV deficiency v5.3 COX18 Ida Ertmanska Phenotypes for gene: COX18 were changed from mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626 to mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626; Charcot-Marie-Tooth disease, axonal, type 2MM, OMIM:621488
Palmoplantar keratodermas v4.14 CAST Ida Ertmanska Phenotypes for gene: CAST were changed from Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads to Peeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, OMIM:616295
Likely inborn error of metabolism v9.13 ASPA Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
Likely inborn error of metabolism v9.13 ASPA Ida Ertmanska Phenotypes for gene: ASPA were changed from Canavan disease to Canavan disease, OMIM:271900
White matter disorders and cerebral calcification - narrow panel v8.5 ASPA Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated.
White matter disorders and cerebral calcification - narrow panel v8.5 ASPA Ida Ertmanska Phenotypes for gene: ASPA were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy, 25655951 to Canavan disease, OMIM:271900
Hereditary neuropathy or pain disorder v8.6 ARHGAP19 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Hereditary neuropathy or pain disorder v8.6 ARHGAP19 Ida Ertmanska Phenotypes for gene: ARHGAP19 were changed from motor peripheral neuropathy, MONDO:0002316 to motor peripheral neuropathy, MONDO:0002316; Charcot-Marie-Tooth disease, axonal, type 2KK, OMIM:621466
Hereditary neuropathy v1.509 ARHGAP19 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Hereditary neuropathy v1.509 ARHGAP19 Ida Ertmanska Phenotypes for gene: ARHGAP19 were changed from motor peripheral neuropathy, MONDO:0002316 to motor peripheral neuropathy, MONDO:0002316; Charcot-Marie-Tooth disease, axonal, type 2KK, OMIM:621466
Ataxia and cerebellar anomalies - narrow panel v9.4 HMBS Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotypes updated 25th Jun 2026.
Ataxia and cerebellar anomalies - narrow panel v9.4 HMBS Ida Ertmanska Phenotypes for gene: HMBS were changed from Leukoencephalopathy, HP:0002352; cerebellar ataxia, MONDO:0000437 to Leukoencephalopathy, HP:0002352; cerebellar ataxia, MONDO:0000437; Leukoencephalopathy, porphyria-related, OMIM:620711; Encephalopathy, porphyria-related, OMIM:620704
White matter disorders and cerebral calcification - narrow panel v8.4 HMBS Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
White matter disorders and cerebral calcification - narrow panel v8.4 HMBS Ida Ertmanska Phenotypes for gene: HMBS were changed from Leukoencephalopathy, HP:0002352 to Leukoencephalopathy, HP:0002352; Leukoencephalopathy, porphyria-related, OMIM:620711
Skeletal ciliopathies v7.1 RSG1 Ida Ertmanska Tag gene-checked tag was added to gene: RSG1.
Limb disorders v8.14 RSG1 Ida Ertmanska Tag gene-checked tag was added to gene: RSG1.
Early onset or syndromic epilepsy v9.17 SNX27 Ida Ertmanska Tag gene-checked was removed from gene: SNX27.
Intellectual disability v10.32 SNX27 Ida Ertmanska Tag gene-checked was removed from gene: SNX27.
Early onset or syndromic epilepsy v9.17 SNX27 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Early onset or syndromic epilepsy v9.17 SNX27 Ida Ertmanska Phenotypes for gene: SNX27 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Damseh-Danson neurodevelopmental disorder, OMIM:621591
Intellectual disability v10.32 SNX27 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Intellectual disability v10.32 SNX27 Ida Ertmanska Phenotypes for gene: SNX27 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Damseh-Danson neurodevelopmental disorder, OMIM:621591
Retinal disorders v9.9 RNU6-9 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Retinal disorders v9.9 RNU6-9 Ida Ertmanska Phenotypes for gene: RNU6-9 were changed from retinitis pigmentosa, MONDO:0019200 to retinitis pigmentosa, MONDO:0019200; Retinitis pigmentosa 106, OMIM:621564
Retinal disorders v9.8 RNU6-8 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Retinal disorders v9.8 RNU6-8 Ida Ertmanska Phenotypes for gene: RNU6-8 were changed from retinitis pigmentosa, MONDO:0019200 to retinitis pigmentosa, MONDO:0019200; Retinitis pigmentosa 105, OMIM:621563
Retinal disorders v9.7 RNU6-2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th Jun 2026.
Retinal disorders v9.7 RNU6-2 Ida Ertmanska Phenotypes for gene: RNU6-2 were changed from retinitis pigmentosa, MONDO:0019200 to retinitis pigmentosa, MONDO:0019200; Retinitis pigmentosa 104, OMIM:621562
Paediatric or syndromic cardiomyopathy v8.4 NRAP Ida Ertmanska Tag gene-checked was removed from gene: NRAP.
Dilated and arrhythmogenic cardiomyopathy v4.3 NRAP Ida Ertmanska Tag gene-checked was removed from gene: NRAP.
Dilated and arrhythmogenic cardiomyopathy v4.3 NRAP Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th June 2026.
Dilated and arrhythmogenic cardiomyopathy v4.3 NRAP Ida Ertmanska Phenotypes for gene: NRAP were changed from Dilated cardiomyopathy, MONDO:0005021 to Dilated cardiomyopathy, MONDO:0005021; Cardiomopathy, dilated, 2N, OMIM:621595
Paediatric or syndromic cardiomyopathy v8.4 NRAP Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th June 2026.
Paediatric or syndromic cardiomyopathy v8.4 NRAP Ida Ertmanska Phenotypes for gene: NRAP were changed from Dilated cardiomyopathy, MONDO:0005021 Edit to Dilated cardiomyopathy, MONDO:0005021; Cardiomopathy, dilated, 2N, OMIM:621595
DDG2P v7.7 LRRC56 Ida Ertmanska Tag gene-checked tag was added to gene: LRRC56.
Early onset or syndromic epilepsy v9.16 H3F3B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 25th June 2026.
Early onset or syndromic epilepsy v9.16 H3F3B Ida Ertmanska Phenotypes for gene: H3F3B were changed from Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies; Bryant-Li-Bhoj neurodevelopmental syndrome 2, OMIM:619721
Intellectual disability v10.31 H3F3B Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 25th June 2026.
Intellectual disability v10.31 H3F3B Ida Ertmanska Phenotypes for gene: H3F3B were changed from Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies; Bryant-Li-Bhoj neurodevelopmental syndrome 2, OMIM:619721
Amelogenesis imperfecta v4.37 FAM83H Ida Ertmanska Tag new-gene-name tag was added to gene: FAM83H.
Congenital muscular dystrophy v7.26 MCOLN1 Eleanor Williams changed review comment from: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.

In addition, as this is a syndromic condition, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel. ; to: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.

In addition, as this is a syndromic condition, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy/dystrophy being a less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel.
Congenital myopathy v7.77 MCOLN1 Eleanor Williams changed review comment from: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.

However, as this is a syndromic presentation, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel. ; to: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.

In addition, as this is a syndromic condition, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel.
Congenital muscular dystrophy v7.26 MCOLN1 Eleanor Williams changed review comment from: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.; to: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.

In addition, as this is a syndromic condition, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel.
Congenital myopathy v7.77 MCOLN1 Eleanor Williams changed review comment from: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.; to: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.

However, as this is a syndromic presentation, with intellectual disability and ophthalmologic abnormalities being the most consistently reported phenotypes, with myopathy being less consistently reported secondary feature, it is more appropriate for this gene to be tested through the Paediatric disorders superpanel as per National Genomic Test Directory recommendations (TD v9). The gene is already green on both the Intellectual disability and Likely inborn error of metabolism panels which are components of the the Paediatric disorders superpanel. The gene is also green on the Lysosomal storage disorder panel.
Clefting v7.7 SF3B1 Ida Ertmanska Classified gene: SF3B1 as Amber List (moderate evidence)
Clefting v7.7 SF3B1 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with clefting / high-arched palate seen in 12/26 patients. Based on available evidence, this gene can be promoted to Green at the next update.
Clefting v7.7 SF3B1 Ida Ertmanska Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.15 SF3B1 Ida Ertmanska Classified gene: SF3B1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.15 SF3B1 Ida Ertmanska Added comment: Comment on list classification: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1 presenting with syndromic ID/GDD, with 13 individuals reported to have seizures. Based on available evidence, this gene can be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.15 SF3B1 Ida Ertmanska Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Clefting v7.6 SF3B1 Ida Ertmanska gene: SF3B1 was added
gene: SF3B1 was added to Clefting. Sources: Literature
Q2_26_promote_green tags were added to gene: SF3B1.
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B1 were set to 25363760; 28135719; 41577671
Phenotypes for gene: SF3B1 were set to Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: SF3B1 was set to GREEN
Added comment: As reviewed by Karen Stals, Uguen et al. (PMID: 41577671, 2026) reported 26 patients with heterozygous SF3B1 variants. Most of them were confirmed to be de novo, with 3 cases where variant was inherited from a parent (2 parents with learning difficulties, and 1 asymptomatic father). Seq method: Trio or Solo WES. 3 patients had VUS variants in other genes.
"Almost all (23/26) affected individuals exhibited at least one neurodevelopmental abnormality, the most frequent being language delay (21/26). Motor delay was found in 18/24 individuals. Intellectual disability (ID) was present in 9/15 individuals, some cases being too young (8/26) to assess. The severity of ID was mainly mild to moderate, only two individuals presenting with severe ID. Seizures were reported in 13 individuals, with variable ages of onset and types." Other features: hypotonia (11 patients), spastic quadriplegia (2 patients without NDD), non-specific brain MRI anomalies (4 cases), cleft palate or high-arched palate (12 patients), heart defects (8/25), postnatal short stature (6), IUGR (5), microcephaly (7/22 assessed).

De novo missense variants in the SF3B1 gene have also been identified in ASD probands (PMID: 25363768 Iossifov et al., 2014 - 2 probands with ASD, harbouring SF3B1 variants c.1078A>G, p.Ile360Val & c.890C>A, p.Pro297His) and two probands with unspecified developmental disorders, with de novo SF3B1 variants c.1108C>T, p.Pro370Ser & c.1781G>A, p.Arg594Gln (PMID: 28135719 Deciphering Developmental Disorders Study 2017).

SF3B1 is not yet associated with an NDD in OMIM, and it has not been classified in ClinGen (accessed 17th Jun 2026). The gene is Green in PanelApp Australia on 'Intellectual disability syndromic and non-syndromic' panel.
Sources: Literature
Early onset or syndromic epilepsy v9.14 SF3B1 Ida Ertmanska gene: SF3B1 was added
gene: SF3B1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_26_promote_green tags were added to gene: SF3B1.
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B1 were set to 25363760; 28135719; 41577671
Phenotypes for gene: SF3B1 were set to Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: SF3B1 was set to GREEN
Added comment: As reviewed by Karen Stals, Uguen et al. (PMID: 41577671, 2026) reported 26 patients with heterozygous SF3B1 variants. Most of them were confirmed to be de novo, with 3 cases where variant was inherited from a parent (2 parents with learning difficulties, and 1 asymptomatic father). Seq method: Trio or Solo WES. 3 patients had VUS variants in other genes.
"Almost all (23/26) affected individuals exhibited at least one neurodevelopmental abnormality, the most frequent being language delay (21/26). Motor delay was found in 18/24 individuals. Intellectual disability (ID) was present in 9/15 individuals, some cases being too young (8/26) to assess. The severity of ID was mainly mild to moderate, only two individuals presenting with severe ID. Seizures were reported in 13 individuals, with variable ages of onset and types." Other features: hypotonia (11 patients), spastic quadriplegia (2 patients without NDD), non-specific brain MRI anomalies (4 cases), cleft palate or high-arched palate (12 patients), heart defects (8/25), postnatal short stature (6), IUGR (5), microcephaly (7/22 assessed).

De novo missense variants in the SF3B1 gene have also been identified in ASD probands (PMID: 25363768 Iossifov et al., 2014 - 2 probands with ASD, harbouring SF3B1 variants c.1078A>G, p.Ile360Val & c.890C>A, p.Pro297His) and two probands with unspecified developmental disorders, with de novo SF3B1 variants c.1108C>T, p.Pro370Ser & c.1781G>A, p.Arg594Gln (PMID: 28135719 Deciphering Developmental Disorders Study 2017).

SF3B1 is not yet associated with an NDD in OMIM, and it has not been classified in ClinGen (accessed 17th Jun 2026). The gene is Green in PanelApp Australia on 'Intellectual disability syndromic and non-syndromic' panel.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.11 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 pateint, who was previolusly 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 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.
Rhabdomyolysis and metabolic muscle disorders v6.6 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 pateint, who was previolusly 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 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.
Distal myopathies v7.4 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 pateint, who was previolusly 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 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.
Congenital muscular dystrophy v7.26 TCAP Achchuthan Shanmugasundram Phenotypes for gene: TCAP were changed from Muscular dystrophy, limb-girdle, autosomal recessive 7, OMIM:601954 to Muscular dystrophy, limb-girdle, autosomal recessive 7, OMIM:601954; autosomal recessive limb-girdle muscular dystrophy type 2G, MONDO:0011170
Congenital muscular dystrophy v7.25 TCAP Achchuthan Shanmugasundram Publications for gene: TCAP were set to 23479141; 21530252; 18948002; 25055047; 29797799; 29935994; 32761539; 36463458; 37216648; 39015008
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Anna Sarkozy, there are at least ten peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decade of life. Although there are several patients reported with early/ childhood-onset, there is only patient from PMID:21530252 (2011) reported with onset in infancy and identified with biallelic TCAP variant. This gene is already green in R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Hence, this gene should remain amber on this panel with the current evidence.; to: Comment on list classification: There are at least ten peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decades of life. Although there are several patients reported with early/ childhood-onset muscular dystrophy, there is only patient from PMID:21530252 (2011) reported with onset in infancy and identified with biallelic TCAP variant.

This gene is already green on 'R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies' panel. As reviewed by Anna Sarkozy, this gene should remain amber on this panel with the current evidence.
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Anna Sarkozy, there are at least eight peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decade of life. Although there are several patients reported with childhood-onset, there is only patient from PMID:36463458 (2023) reported with onset in infancy. This gene is already green in R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Hence, this gebne should remina amber with current evidnece.; to: Comment on list classification: As reviewed by Anna Sarkozy, there are at least ten peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decade of life. Although there are several patients reported with early/ childhood-onset, there is only patient from PMID:21530252 (2011) reported with onset in infancy and identified with biallelic TCAP variant. This gene is already green in R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Hence, this gene should remain amber on this panel with the current evidence.
Early onset or syndromic epilepsy v9.13 MED17 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated families where affected individuals harboured biallelic MED17 variants and presented with seizures (among other syndromic symptoms). Based on available evidence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are 3 unrelated families (Jewish families with potential founder variant counted as one) where affected individuals harboured biallelic MED17 variants and presented with seizures (among other syndromic symptoms). Based on available evidence, this gene can be promoted to Green at the next update.
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram edited their review of gene: TCAP: Changed publications to: 18948002, 21530252, 23479141, 25055047, 29797799, 29935994, 32761539, 36463458, 37216648, 39015008
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram edited their review of gene: TCAP: Changed publications to: 18948002, 21530252, 25055047, 29797799, 29935994, 32761539, 36463458, 37216648, 39015008
Congenital muscular dystrophy v7.24 TCAP Achchuthan Shanmugasundram Publications for gene: TCAP were set to 23479141; 21530252
Congenital muscular dystrophy v7.23 TCAP Achchuthan Shanmugasundram Classified gene: TCAP as Amber List (moderate evidence)
Congenital muscular dystrophy v7.23 TCAP Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Anna Sarkozy, there are at least eight peer-reviewed scientific publications with over 80 reported patients from multiple descents/ geographic locations with autosomal recessive limb-girdle muscular dystrphy 7 (MIM #601954).

The phenotype includes progressive proximal lower limb muscle weakness with typical disease onset is in first to third decade of life. Although there are several patients reported with childhood-onset, there is only patient from PMID:36463458 (2023) reported with onset in infancy. This gene is already green in R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Hence, this gebne should remina amber with current evidnece.
Congenital muscular dystrophy v7.23 TCAP Achchuthan Shanmugasundram Gene: tcap has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v7.22 TCAP Achchuthan Shanmugasundram reviewed gene: TCAP: Rating: AMBER; Mode of pathogenicity: None; Publications: 18948002, 25055047, 29797799, 29935994, 32761539, 36463458, 37216648, 39015008; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 7, OMIM:601954, autosomal recessive limb-girdle muscular dystrophy type 2G, MONDO:0011170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.30 GIGYF1 Jana Jezkova reviewed gene: GIGYF1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35917186, 36924980, 36189799, 31439631; Phenotypes: ASD, NDD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Amelogenesis imperfecta v4.37 FAM83H Ida Ertmanska commented on gene: FAM83H
Adult solid tumours cancer susceptibility v2.40 CHEK2 Arina Puzriakova Publications for gene: CHEK2 were set to 40335619
Inherited predisposition to acute myeloid leukaemia (AML) v3.10 CHEK2 Arina Puzriakova Publications for gene: CHEK2 were set to 29902706
Inherited predisposition to acute myeloid leukaemia (AML) v3.9 CHEK2 Arina Puzriakova Phenotypes for gene: CHEK2 were changed from 609265 Li-Fraumeni syndrome; 609265 (OMIM phenotype description ID) to Hematologic malignancy predisposition; Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265
Rhabdomyolysis and metabolic muscle disorders v6.6 DYSF Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least 6 unrelated families with heterozygous carrier individuals presenting with a limb-girdle muscular dystrophy/ distal myopathy phenotype despite it being milder and later-onset than individuals with biallelic variants. There is also evidence of some heterozygous carriers from two of the families not displaying phenotype suggesting reduced penetrance.

As there are six unrelated families with monoalellic phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.
Rhabdomyolysis and metabolic muscle disorders v6.6 DYSF Achchuthan Shanmugasundram Mode of inheritance for gene: DYSF was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v6.5 DYSF Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: DYSF.
Rhabdomyolysis and metabolic muscle disorders v6.5 DYSF Achchuthan Shanmugasundram commented on gene: DYSF: 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 pateint, who was previolusly 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.
Rhabdomyolysis and metabolic muscle disorders v6.5 DYSF Achchuthan Shanmugasundram Publications for gene: DYSF were set to 25929793
Rhabdomyolysis and metabolic muscle disorders v6.4 DYSF Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Biallelic variants in DYSF gene are associated with relevant phenotypes in OMIM (MIMs #253601, #254130 & #606768) and the records were last accessed 25 June 2026.

Biallelic DYSF variants are also associated with AR limb-girdle muscular dystrophy with 'Definitive' rating by the Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004715).
Rhabdomyolysis and metabolic muscle disorders v6.4 DYSF Achchuthan Shanmugasundram Phenotypes for gene: DYSF were changed from Miyoshi muscular dystrophy 1, OMIM:254130; Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601; Myopathy, distal, with anterior tibial onset, OMIM:606768 to Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601; Miyoshi muscular dystrophy 1, OMIM:254130; Myopathy, distal, with anterior tibial onset, OMIM:606768
Rhabdomyolysis and metabolic muscle disorders v6.3 DYSF Achchuthan Shanmugasundram reviewed gene: DYSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 17287450, 21658164, 29879922, 35962550; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601, Miyoshi muscular dystrophy 1, OMIM:254130, Myopathy, distal, with anterior tibial onset, OMIM:606768; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Distal myopathies v7.4 DYSF Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least 6 unrelated families with heterozygous carrier individuals presenting with a limb-girdle muscular dystrophy/ distal myopathy phenotype despite it being milder and later-onset than individuals with biallelic variants. There is also evidence of some heterozygous carriers from two of the families not displaying phenotype suggesting reduced penetrance.

As there are six unrelated families with monoalellic phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.
Distal myopathies v7.4 DYSF Achchuthan Shanmugasundram Mode of inheritance for gene: DYSF was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.11 DYSF Achchuthan Shanmugasundram Publications for gene: DYSF were set to http://www.ncbi.nlm.nih.gov/books/NBK1408/
Distal myopathies v7.3 DYSF Achchuthan Shanmugasundram Publications for gene: DYSF were set to 20301480
Distal myopathies v7.2 DYSF Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: DYSF.
Distal myopathies v7.2 DYSF Achchuthan Shanmugasundram edited their review of gene: DYSF: Added comment: 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 pateint, who was previolusly 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.; Changed rating: GREEN; Changed publications to: 17287450, 21658164, 29879922, 35962550; Changed phenotypes to: Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601, Miyoshi muscular dystrophy 1, OMIM:254130, Myopathy, distal, with anterior tibial onset, OMIM:606768; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Distal myopathies v7.2 DYSF Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Biallelic variants in DYSF gene are associated with relevant phenotypes in OMIM (MIMs #253601, #254130 & #606768) and the records were last accessed 25 June 2026. Biallelic DYSF variants are also associated with AR limb-girdle muscular dystrophy with 'Definitive' rating by the Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004715).
Distal myopathies v7.2 DYSF Achchuthan Shanmugasundram Phenotypes for gene: DYSF were changed from Miyoshi muscular dystrophy 1, 254130 to Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601; Miyoshi muscular dystrophy 1, OMIM:254130; Myopathy, distal, with anterior tibial onset, OMIM:606768
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.10 DYSF Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are at least 6 unrelated families with heterozygous carrier individuals presenting with a limb-girdle muscular dystrophy/ myopathy phenotype despite it being milder and later-onset than individuals with biallelic variants. There is also evidence of some heterozygous carriers from two of the families not displaying phenotype suggesting reduced penetrance.

As there are six unrelated families with monoalellic phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.10 DYSF Achchuthan Shanmugasundram Mode of inheritance for gene: DYSF was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.9 DYSF Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: DYSF.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.9 DYSF Achchuthan Shanmugasundram edited their review of gene: DYSF: Added comment: 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 pateint, who was previolusly 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.; Changed publications to: 17287450, 21658164, 29879922, 35962550; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.9 DYSF Achchuthan Shanmugasundram Deleted their comment
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen.; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen or Gene2Phenotype.
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026).; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026). The gene is Amber on the Optic atrophy panel in PanelApp Australia, and it has not been curated in ClinGen.
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly variant specific phenotype?; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly a variant-specific phenotype.
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - variant specific phenotype?; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - possibly variant specific phenotype?
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188).; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy (PMID: 21282188) - variant specific phenotype?
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected. ; to: PMID: 41045073 Valentin et al., 2025 (journal pre-proof)
Authors report 19 individuals from 9 families (8 European / Austrian and 1 East Asian / Thai) affected by isolated optic neuropathy. Affected individuals were heterozygous for PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp)]. Sequencing method: exome sequencing. Median age of onset was 36 years old (range 14-58 yo), with variable severity. Haplotype analysis revealed that the variant in PPIB is present on a common ancestral haplotype in 5/9 families.
In addition, genotyping of family members revealed 6 unaffected individuals were heterozygous for p.(Arg180Trp). Age range: 6-26 years old - possibly assessed before onset of disease.
The mRNA and protein levels were the same between fibroblasts of affected and unaffected members. Mitochondrial morphology investigation showed that affected individuals had a higher proportion of fragmented, 'balloon-like' mitochondria. Some evidence of decreased respiration rate and ATP production rate in affected individuals.
PPIB [NM_000942.5:c.538C>T, p.(Arg180Trp) - Revel score = 0.16 (Benign); rare in gnomAD v4, 7 heterozygotes reported. The variant lies in the last exon of PPIB at the end of the predicted Pro_isomerase functional domain (Decipher).

PMID: 21282188 Pyott et al., 2011
3 families with individuals affected by osteogenesis imperfecta, with biallelic variants in PPIB.
Family 1: c.120delC, p.(Val42SerfsX16), P1 and affected sister homozygous, parents confirmed heterozygous.
Family 2: 2 siblings compound heterozygous for c.414_423del, p.(Ser139Thrfs*21) and c.313G>A, p.(Gly105Arg). Parents confirmed heterozygous for one allele each.
Family 3: proband homozygous for c.343+1G>A, p.(Gly115delins10) - parents not genotyped.
Expression studies of mutant transcripts confirmed that mRNA and/or protein levels were unstable. Heterozygous parents were reported to be unaffected.

PPIB is associated with AR Osteogenesis imperfecta, type IX, MIM:259440 in OMIM (accessed 25th June 2026).
Optic neuropathy v6.43 PPIB Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: PPIB.
Tag Q2_26_expert_review tag was added to gene: PPIB.
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.
However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188).; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.

However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188).
Optic neuropathy v6.43 PPIB Ida Ertmanska changed review comment from: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. As 8/9 families are of European (Austrian) origins, a founder variant effect cannot be excluded.
Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188). Based on the available evidence, this gene-disease association is ambiguous and should be rated as Amber.; to: Comment on list classification: There is emerging evidence for the association of optic neuropathy and monoallelic variants in PPIB. 19 individuals from 9 families, affected by isolated optic neuropathy, were heterozygous for the same variant in PPIB: c.538C>T, p.(Arg180Trp) - PMID: 41045073. Hence, PPIB can be promoted to Green on Optic neuropathy at the next update.
However, this association is also tagged for expert review, due to some confounding evidence about the variant. As 8/9 families are of European (Austrian) origins, a founder effect is possible - though haplotype analysis showed the variant is on a different haplotype in 3 families. PPIB p.Arg180Trp variant also has a Benign (0.16) Revel prediction, VUS rating in ClinVar, and 7 heterozygotes (6 European) reported in gnomAD v4. Moreover, biallelic variants in PPIB have previously been implicated in severe skeletal dysplasia / osteogenesis imperfecta, with no mention of optic atrophy symptoms in the heterozygous family members (PMID: 21282188).
Optic neuropathy v6.43 PPIB Ida Ertmanska edited their review of gene: PPIB: Changed rating: GREEN
Blepharophimosis ptosis and epicanthus inversus v1.5 Achchuthan Shanmugasundram List of related panels changed from R43; GT841; TP355 to R43; GT688; TP68
Non-acute porphyrias v1.42 HMBS Arina Puzriakova changed review comment from: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.; to: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
DDG2P v7.7 GNAS Arina Puzriakova Deleted their comment
DDG2P v7.7 GNAS Arina Puzriakova Deleted their comment
DDG2P v7.7 GNAS Arina Puzriakova Deleted their comment
Renal tubulopathies v6.7 GNAS Arina Puzriakova Deleted their comment
Renal tubulopathies v6.7 GNAS Arina Puzriakova Deleted their comment
Renal tubulopathies v6.7 GNAS Arina Puzriakova Deleted their comment
Skeletal dysplasia v9.20 GNAS Arina Puzriakova Deleted their comment
Skeletal dysplasia v9.20 GNAS Arina Puzriakova Deleted their comment
Skeletal dysplasia v9.20 GNAS Arina Puzriakova Deleted their comment
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 GNAS Arina Puzriakova Deleted their comment
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 GNAS Arina Puzriakova Deleted their comment
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 GNAS Arina Puzriakova Deleted their comment
Osteogenesis imperfecta v6.7 GNAS Arina Puzriakova Deleted their comment
Osteogenesis imperfecta v6.7 GNAS Arina Puzriakova Deleted their comment
Osteogenesis imperfecta v6.7 GNAS Arina Puzriakova Deleted their comment
Limb disorders v8.14 GNAS Arina Puzriakova Deleted their comment
Limb disorders v8.14 GNAS Arina Puzriakova Deleted their comment
Limb disorders v8.14 GNAS Arina Puzriakova Deleted their comment
Cholestasis v4.11 GNAS Arina Puzriakova Deleted their comment
Cholestasis v4.11 GNAS Arina Puzriakova Deleted their comment
Cholestasis v4.11 GNAS Arina Puzriakova Deleted their comment
Fetal anomalies v7.21 GNAS Arina Puzriakova Deleted their comment
Fetal anomalies v7.21 GNAS Arina Puzriakova Deleted their comment
Fetal anomalies v7.21 GNAS Arina Puzriakova Deleted their comment
Severe early-onset obesity v6.7 GNAS Arina Puzriakova Deleted their comment
Severe early-onset obesity v6.7 GNAS Arina Puzriakova Deleted their comment
Severe early-onset obesity v6.7 GNAS Arina Puzriakova Deleted their comment
Congenital hypothyroidism v3.10 GNAS Arina Puzriakova Deleted their comment
Congenital hypothyroidism v3.10 GNAS Arina Puzriakova Deleted their comment
Congenital hypothyroidism v3.10 GNAS Arina Puzriakova Deleted their comment
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.16 GNAS Arina Puzriakova Deleted their comment
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.16 GNAS Arina Puzriakova Deleted their comment
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.16 GNAS Arina Puzriakova Deleted their comment
Intellectual disability v10.30 GNAS Arina Puzriakova Deleted their comment
Intellectual disability v10.30 GNAS Arina Puzriakova Deleted their comment
Intellectual disability v10.30 GNAS Arina Puzriakova Deleted their comment
Pigmentary skin disorders v5.9 GNAS Arina Puzriakova Deleted their comment
Pigmentary skin disorders v5.9 GNAS Arina Puzriakova Deleted their comment
Pigmentary skin disorders v5.9 GNAS Arina Puzriakova Deleted their comment
Mosaic skin disorders - deep sequencing v3.33 GNAS Arina Puzriakova Deleted their comment
Mosaic skin disorders - deep sequencing v3.33 GNAS Arina Puzriakova Deleted their comment
Mosaic skin disorders - deep sequencing v3.33 GNAS Arina Puzriakova Deleted their comment
Non-acute porphyrias v1.42 HMBS Arina Puzriakova Tag Q2_26_MOI was removed from gene: HMBS.
Non-acute porphyrias v1.42 HMBS Arina Puzriakova Deleted their comment
Non-acute porphyrias v1.42 HMBS Arina Puzriakova Deleted their comment
Non-acute porphyrias v1.42 HMBS Arina Puzriakova Deleted their comment
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova Tag Q2_26_demote_red was removed from gene: DNMT3A.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova Deleted their comment
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova Deleted their comment
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova Deleted their comment
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova Tag Q2_26_demote_red was removed from gene: AMPD1.
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova Deleted their comment
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova Deleted their comment
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova Deleted their comment
DDG2P v7.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Renal tubulopathies v6.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Skeletal dysplasia v9.20 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.11 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Osteogenesis imperfecta v6.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Limb disorders v8.14 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Cholestasis v4.11 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Fetal anomalies v7.21 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Severe early-onset obesity v6.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Congenital hypothyroidism v3.10 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.16 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Intellectual disability v10.30 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Pigmentary skin disorders v5.9 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Mosaic skin disorders - deep sequencing v3.33 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Non-acute porphyrias v1.42 HMBS Arina Puzriakova commented on gene: HMBS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.8 DNMT3A Arina Puzriakova commented on gene: DNMT3A: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
Acute rhabdomyolysis v2.16 AMPD1 Arina Puzriakova commented on gene: AMPD1: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
DDG2P v7.6 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Renal tubulopathies v6.6 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Skeletal dysplasia v9.19 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.10 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Osteogenesis imperfecta v6.6 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Limb disorders v8.13 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Cholestasis v4.10 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Fetal anomalies v7.20 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Severe early-onset obesity v6.6 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Congenital hypothyroidism v3.9 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.15 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Intellectual disability v10.29 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Pigmentary skin disorders v5.8 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Mosaic skin disorders - deep sequencing v3.32 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Non-acute porphyrias v1.41 HMBS Arina Puzriakova commented on gene: HMBS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.7 DNMT3A Arina Puzriakova commented on gene: DNMT3A: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
Acute rhabdomyolysis v2.15 AMPD1 Arina Puzriakova commented on gene: AMPD1: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
DDG2P v7.5 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Renal tubulopathies v6.5 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Skeletal dysplasia v9.18 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.9 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Osteogenesis imperfecta v6.5 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Limb disorders v8.12 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Cholestasis v4.9 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Fetal anomalies v7.19 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Severe early-onset obesity v6.5 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Congenital hypothyroidism v3.8 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.14 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Intellectual disability v10.28 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Pigmentary skin disorders v5.7 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Mosaic skin disorders - deep sequencing v3.31 GNAS Arina Puzriakova commented on gene: GNAS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Non-acute porphyrias v1.40 HMBS Arina Puzriakova commented on gene: HMBS: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.6 DNMT3A Arina Puzriakova commented on gene: DNMT3A: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
Acute rhabdomyolysis v2.14 AMPD1 Arina Puzriakova commented on gene: AMPD1: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
DDG2P v7.4 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Renal tubulopathies v6.4 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Skeletal dysplasia v9.17 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.8 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Osteogenesis imperfecta v6.4 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Limb disorders v8.11 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Cholestasis v4.8 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Fetal anomalies v7.18 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Severe early-onset obesity v6.4 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Congenital hypothyroidism v3.7 GNAS Arina Puzriakova edited their review of gene: GNAS: Added comment: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.; Changed mode of inheritance: Unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.13 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Intellectual disability v10.27 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Pigmentary skin disorders v5.6 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Mosaic skin disorders - deep sequencing v3.30 GNAS Arina Puzriakova reviewed gene: GNAS: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Non-acute porphyrias v1.39 HMBS Arina Puzriakova edited their review of gene: HMBS: Added comment: The mode of inheritance of this gene has been updated to Unknown following NHS Genomic Medicine Service approval. This mode of inheritance enables inclusive tiering across all segregation patterns for this gene.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.5 DNMT3A Arina Puzriakova edited their review of gene: DNMT3A: Added comment: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.; Changed rating: RED
Acute rhabdomyolysis v2.13 AMPD1 Arina Puzriakova commented on gene: AMPD1: The rating of this gene has been updated to Red following NHS Genomic Medicine Service approval.
DDG2P v7.3 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Renal tubulopathies v6.3 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to Unknown
Skeletal dysplasia v9.16 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.7 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed) to Unknown
Osteogenesis imperfecta v6.3 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from to Unknown
Limb disorders v8.10 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Cholestasis v4.7 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Unknown
Fetal anomalies v7.17 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Severe early-onset obesity v6.3 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Congenital hypothyroidism v3.6 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.12 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Intellectual disability v10.26 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Pigmentary skin disorders v5.5 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Mosaic skin disorders - deep sequencing v3.29 GNAS Arina Puzriakova Mode of inheritance for gene GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
Non-acute porphyrias v1.38 HMBS Arina Puzriakova Mode of inheritance for gene HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.4 DNMT3A Arina Puzriakova Source Expert Review Red was added to DNMT3A.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Acute rhabdomyolysis v2.12 AMPD1 Arina Puzriakova Source Expert Review Red was added to AMPD1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.16 BIRC3 Boaz Palterer gene: BIRC3 was added
gene: BIRC3 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: BIRC3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: BIRC3 were set to Inflammatory bowel disease; IBD; Crohn's disease
Penetrance for gene: BIRC3 were set to unknown
Review for gene: BIRC3 was set to GREEN
Added comment: Qi Li et al. described 14 patients from 10 unrelated families with monoallelic and biallelic variants in BIRC3 presenting with CD. Biallelic variants present more severe and earlier. Extensive funtional validation including zebrafish and mice models, recapitulating phenotype
https://www.gastrojournal.org/article/S0016-5085(26)06946-5/fulltext
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v5.2 Eleanor Williams List of related panels changed from R189 to R189; GT67; TP149
Pulmonary fibrosis familial v1.11 Eleanor Williams List of related panels changed from R421 to R421; GT1047; TP235
Pulmonary arterial hypertension v4.12 Eleanor Williams List of related panels changed from PAH; R188 to PAH; R188; GT412; TP299
Pulmonary alveolar microlithiasis v1.4 Eleanor Williams List of related panels changed from R426 to R426; GT1005; TP491
Pneumothorax - familial v3.7 Eleanor Williams List of related panels changed from Familial Pneumothorax; Familial Primary Spontaneous Pneumothorax; R190 to Familial Pneumothorax; Familial Primary Spontaneous Pneumothorax; R190; GT843; TP219
Laterality disorders and isomerism v5.2 Eleanor Williams List of related panels changed from R139 to R139; GT588; TP531
Hereditary haemorrhagic telangiectasia v3.8 Eleanor Williams List of related panels changed from Familial and multiple pulmonary arteriovenous malformations; R186 to Familial and multiple pulmonary arteriovenous malformations; R186; GT336; TP252
Cystic fibrosis diagnostic test v1.4 Eleanor Williams List of related panels changed from R184 to R184; GT219; TP46
Childhood interstitial lung disease v1.2 Eleanor Williams List of related panels changed from R462 to R462; GT1438; TP109
Central congenital hypoventilation v1.8 Eleanor Williams List of related panels changed from R333 to R333; GT163; TP470
Alveolar capillary dysplasia with misalignment of pulmonary veins v1.9 Eleanor Williams List of related panels changed from R330 to R330; GT755; TP42
Unexplained young onset end-stage renal disease v13.15 Eleanor Williams List of related panels changed from Unexplained paediatric onset end-stage renal disease; R257 to Unexplained paediatric onset end-stage renal disease; R257; GT608; GT787; TP574
Tubulointerstitial kidney disease v3.34 Eleanor Williams List of related panels changed from R202 to R202; GT827; TP233
Renal tubulopathies v6.2 Eleanor Williams List of related panels changed from Renal tubular acidosis; R198 to Renal tubular acidosis; R198; GT1245; TP408
Proteinuric renal disease v6.2 Eleanor Williams List of related panels changed from R195 to R195; GT785; TP484
Nephrocalcinosis or nephrolithiasis v6.2 Eleanor Williams List of related panels changed from Renal tract calcification (or Nephrolithiasis or nephrocalcinosis); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis); R256 to Renal tract calcification (or Nephrolithiasis or nephrocalcinosis); Renal tract calcification (or Nephrolithiasis/nephrocalcinosis); R256; GT28; TP136
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.14 Eleanor Williams List of related panels changed from PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; Membranoproliferative glomerulonephritis; R197 to PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; Membranoproliferative glomerulonephritis; R197; GT704; TP82
Hereditary systemic amyloidosis v1.30 Eleanor Williams List of related panels changed from Amyloidosis; R204 to Amyloidosis; R204; GT199; TP394
Haematuria v2.19 Eleanor Williams List of related panels changed from Alport syndrome; Familial haematuria; R194 to Alport syndrome; Familial haematuria; R194; GT846; TP94
Cystic renal disease v13.4 Eleanor Williams List of related panels changed from Cystic renal disease - PKD1; R193 to Cystic renal disease - PKD1; R193; GT497; TP171
Atypical haemolytic uraemic syndrome v3.10 Eleanor Williams List of related panels changed from R201 to R201; GT997; TP209
Structural eye disease v5.7 Eleanor Williams List of related panels changed from R36 to R36; GT692; TP458
Stickler syndrome v4.9 Eleanor Williams List of related panels changed from R45 to R45; GT654; TP572
Sporadic aniridia v3.7 Eleanor Williams List of related panels changed from Aniridia; R38 to Aniridia; R38; GT663; TP329
Skeletal dysplasia v9.15 Achchuthan Shanmugasundram List of related panels changed from Unexplained skeletal dysplasia; Skeletal dysplasia; R104 to Unexplained skeletal dysplasia; Skeletal dysplasia; R104; GT245; TP399
Short stature - SHOX deficiency v1.4 Achchuthan Shanmugasundram List of related panels changed from R52 to R52; GT920; TP319
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.6 Achchuthan Shanmugasundram List of related panels changed from Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; Craniosynostosis; R100 to Craniosynostosis syndromes; Craniosynostosis syndromes phenotypes; Rare syndromic craniosynostosis or isolated multisuture synostosis; Craniosynostosis; R100; GT241; TP474
Osteopetrosis v2.2 Achchuthan Shanmugasundram List of related panels changed from R104.4 to R104.4; GT167; TP399
Osteogenesis imperfecta v6.2 Achchuthan Shanmugasundram List of related panels changed from Osteogenesis Imperfecta; R102 to Osteogenesis Imperfecta; R102; GT1068; TP505
Retinal disorders v9.6 Eleanor Williams List of related panels changed from Posterior segment abnormalities; Cone Dysfunction Syndrome; Developmental macular and foveal dystrophy; Inherited macular dystrophy; Leber Congenital Amaurosis Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy; Rod Dysfunction Syndrome; Rod-cone dystrophy; Familial exudative vitreoretinopathy; Familial exudative retinopathy; Sorsby retinal dystrophy; Doyne retinal dystrophy; R32 to Posterior segment abnormalities; Cone Dysfunction Syndrome; Developmental macular and foveal dystrophy; Inherited macular dystrophy; Leber Congenital Amaurosis Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy; Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy; Rod Dysfunction Syndrome; Rod-cone dystrophy; Familial exudative vitreoretinopathy; Familial exudative retinopathy; Sorsby retinal dystrophy; Doyne retinal dystrophy; R32; GT1235; TP381
Pseudoxanthoma elasticum v1.5 Eleanor Williams List of related panels changed from R420 to R420; GT375; TP462
Retinal disorders v9.5 Chr17q22 Katie Cox reviewed Region: Chr17q22: Rating: ; Mode of pathogenicity: None; Publications: PMID: 33022222; Phenotypes: RETINITIS PIGMENTOSA 17 (OMIM #600852); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Multiple exostoses v1.5 Achchuthan Shanmugasundram List of related panels changed from R390 to R390; GT1204; TP487
Intestinal failure or congenital diarrhoea v3.13 Arina Puzriakova List of related panels changed from R331; Intestinal failure; GT1311; TP348 to Intestinal failure; R331; GT1311; TP348
Optic neuropathy v6.43 Eleanor Williams List of related panels changed from Inherited optic neuropathies; R41 to Inherited optic neuropathies; R41; GT487; TP247
Ehlers Danlos syndrome with a likely monogenic cause v4.14 Achchuthan Shanmugasundram List of related panels changed from Classical Ehlers Danlos Syndrome; Classical Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome (unusual phenotypes e.g. absent pain sense); Ehlers-Danlos syndrome type 3; Kyphoscoliotic Ehlers-Danlos syndrome; EDS; Ehlers-Danlos syndromes; Ehlers Danlos syndromes; R101 to Classical Ehlers Danlos Syndrome; Classical Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome (unusual phenotypes e.g. absent pain sense); Ehlers-Danlos syndrome type 3; Kyphoscoliotic Ehlers-Danlos syndrome; EDS; Ehlers-Danlos syndromes; Ehlers Danlos syndromes; R101; GT525; TP509
Corneal dystrophy v4.10 Eleanor Williams List of related panels changed from Corneal dystrophies; R262 to Corneal dystrophies; R262; GT1218; TP489
Common craniosynostosis syndromes v1.18 Achchuthan Shanmugasundram List of related panels changed from R99 to R99; GT322; TP134
Congenital fibrosis of the extraocular muscles v2.4 Eleanor Williams List of related panels changed from R46 to R46; GT216; TP77
Amelogenesis imperfecta v4.37 Achchuthan Shanmugasundram List of related panels changed from Amelogenesis Imperfecta; R340 to Amelogenesis Imperfecta; R340; GT464; TP321
Thiamine metabolism dysfunction syndrome 2 v1.4 Achchuthan Shanmugasundram List of related panels changed from R395 to R395; GT285; TP463
Fetal anomalies v7.16 Arina Puzriakova List of related panels changed from R21; Fetal anomalies with a likely genetic cause; Fetal anomalies with a likely genetic cause - non urgent; R412; GT520; TP260; TP416 to Fetal anomalies with a likely genetic cause; R21; Fetal anomalies with a likely genetic cause - non urgent; R412; GT520; TP260; TP416
Ataxia and cerebellar anomalies - narrow panel v9.3 ATP2B2 Christopher Burke gene: ATP2B2 was added
gene: ATP2B2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review
Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Phenotypes for gene: ATP2B2 were set to Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities
Penetrance for gene: ATP2B2 were set to unknown
Review for gene: ATP2B2 was set to GREEN
gene: ATP2B2 was marked as current diagnostic
Added comment: ATP2B2 is associated with Deafness, autosomal dominant 82 (OMIM 619804) in OMIM. Emerging evidence suggests that heterozygous pathogenic variants in ATP2B2 can cause a neurodevelopmental phenotype.

Recent papers have outlined and extended neurodevelopmental phenotype (PMID: 39367743, PMID: 37675773, PMID: 29655659) not documented in OMIM or G2P. Summarised phenotypes from 14 reported individuals (13 unrelated individuals) - Global developmental delay (12/14), delayed motor development (12/14), ataxia (9/14), impaired speech (13/14), intellectual disability (13/14), cerebellar atrophy (4/14), behavioural issues (9/14), seizures (9/14), hypotonia (6/14), dysmorphic features (4/14), hearing abnormalities (3/14), and ophthalmological abnormalities (6/14).

PMID: 29655659 - Heterozygous missense. Targeted NGS, unknown inheritance.

PMID: 37675773 - Trio exome sequencing for families 1-6, confirmed de novo status for all 6 families. Seventh family could not be confirmed. 5 missense variants, 2 frameshift variants.

PMID: 39367743 - Trio exome sequencing for families 1-4, confirmed de novo in all 4 families. One case paternally inherited, one unknown. 4 missense variants, 1 frameshift variant (2 individuals in the same family).

ATP2B2 is plasma membrane Ca2+ ATPase involved in Ca2+ homeostasis. Ca2+ deregulation in humans and mice can cause cognitive, behavioural, sensory, and movement disorders. Discussed in detail in PMID: 37675773.

Request addition to R27, R29, R55, R59, R69, R84, Ataxia and Cerebellar Anomalies - Narrow Panel.
Sources: Expert Review
Pyruvate dehydrogenase (PDH) deficiency v1.41 Achchuthan Shanmugasundram List of related panels changed from R316 to R316; GT767; TP9
Blepharophimosis ptosis and epicanthus inversus v1.4 Eleanor Williams List of related panels changed from R43 to R43; GT841; TP355
Retinal disorders v9.5 Chr17q22 Katie Cox Deleted their review
Possible mitochondrial disorder - nuclear genes v5.7 Achchuthan Shanmugasundram List of related panels changed from R63 to R63; GT759; TP627
Early onset or syndromic epilepsy v9.13 ATP2B2 Christopher Burke gene: ATP2B2 was added
gene: ATP2B2 was added to Early onset or syndromic epilepsy. Sources: Expert Review
Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Phenotypes for gene: ATP2B2 were set to Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities
Penetrance for gene: ATP2B2 were set to unknown
Review for gene: ATP2B2 was set to GREEN
gene: ATP2B2 was marked as current diagnostic
Added comment: ATP2B2 is associated with Deafness, autosomal dominant 82 (OMIM 619804) in OMIM. Emerging evidence suggests that heterozygous pathogenic variants in ATP2B2 can cause a neurodevelopmental phenotype.

Recent papers have outlined and extended neurodevelopmental phenotype (PMID: 39367743, PMID: 37675773, PMID: 29655659) not documented in OMIM or G2P. Summarised phenotypes from 14 reported individuals (13 unrelated individuals) - Global developmental delay (12/14), delayed motor development (12/14), ataxia (9/14), impaired speech (13/14), intellectual disability (13/14), cerebellar atrophy (4/14), behavioural issues (9/14), seizures (9/14), hypotonia (6/14), dysmorphic features (4/14), hearing abnormalities (3/14), and ophthalmological abnormalities (6/14).

PMID: 29655659 - Heterozygous missense. Targeted NGS, unknown inheritance.

PMID: 37675773 - Trio exome sequencing for families 1-6, confirmed de novo status for all 6 families. Seventh family could not be confirmed. 5 missense variants, 2 frameshift variants.

PMID: 39367743 - Trio exome sequencing for families 1-4, confirmed de novo in all 4 families. One case paternally inherited, one unknown. 4 missense variants, 1 frameshift variant (2 individuals in the same family).

ATP2B2 is plasma membrane Ca2+ ATPase involved in Ca2+ homeostasis. Ca2+ deregulation in humans and mice can cause cognitive, behavioural, sensory, and movement disorders. Discussed in detail in PMID: 37675773.

Request addition to R27, R29, R55, R59, R69, R84, Ataxia and Cerebellar Anomalies - Narrow Panel.
Sources: Expert Review
Bilateral congenital or childhood onset cataracts v8.5 Eleanor Williams List of related panels changed from Cataracts; R31 to Cataracts; R31; GT841; TP355
POLG-related disorder v1.4 Achchuthan Shanmugasundram List of related panels changed from R315 to R315; GT281; TP294
NARP syndrome or maternally inherited Leigh syndrome v2.3 Achchuthan Shanmugasundram List of related panels changed from R351 to R351; GT87; TP207
Bardet Biedl syndrome v2.18 Eleanor Williams List of related panels changed from R107 to R107; GT286; TP326
Intellectual disability v10.25 ATP2B2 Christopher Burke gene: ATP2B2 was added
gene: ATP2B2 was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: ATP2B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B2 were set to PMID: 29655659; 37675773; 39367743
Phenotypes for gene: ATP2B2 were set to Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities
Penetrance for gene: ATP2B2 were set to unknown
Review for gene: ATP2B2 was set to GREEN
gene: ATP2B2 was marked as current diagnostic
Added comment: ATP2B2 is associated with Deafness, autosomal dominant 82 (OMIM 619804) in OMIM. Emerging evidence suggests that heterozygous pathogenic variants in ATP2B2 can cause a neurodevelopmental phenotype.

Recent papers have outlined and extended neurodevelopmental phenotype (PMID: 39367743, PMID: 37675773, PMID: 29655659) not documented in OMIM or G2P. Summarised phenotypes from 14 reported individuals (13 unrelated individuals) - Global developmental delay (12/14), delayed motor development (12/14), ataxia (9/14), impaired speech (13/14), intellectual disability (13/14), cerebellar atrophy (4/14), behavioural issues (9/14), seizures (9/14), hypotonia (6/14), dysmorphic features (4/14), hearing abnormalities (3/14), and ophthalmological abnormalities (6/14).

PMID: 29655659 - Heterozygous missense. Targeted NGS, unknown inheritance.

PMID: 37675773 - Trio exome sequencing for families 1-6, confirmed de novo status for all 6 families. Seventh family could not be confirmed. 5 missense variants, 2 frameshift variants.

PMID: 39367743 - Trio exome sequencing for families 1-4, confirmed de novo in all 4 families. One case paternally inherited, one unknown. 4 missense variants, 1 frameshift variant (2 individuals in the same family).

ATP2B2 is plasma membrane Ca2+ ATPase involved in Ca2+ homeostasis. Ca2+ deregulation in humans and mice can cause cognitive, behavioural, sensory, and movement disorders. Discussed in detail in PMID: 37675773.

Request addition to R27, R29, R55, R59, R69, R84, Ataxia and Cerebellar Anomalies - Narrow Panel.
Sources: Expert Review
Mitochondrial neurogastrointestinal encephalopathy v1.4 Achchuthan Shanmugasundram List of related panels changed from R394 to R394; GT1179; TP267
Albinism or congenital nystagmus v4.12 Eleanor Williams List of related panels changed from R39 to R39; GT1287; TP208
Mitochondrial liver disease, including transient infantile liver failure v1.15 Achchuthan Shanmugasundram List of related panels changed from Mitochondrial liver disease; R317 to Mitochondrial liver disease; R317; GT766; TP167
Mitochondrial DNA maintenance disorder v3.10 Achchuthan Shanmugasundram List of related panels changed from R352 to R352; GT1167; TP138
Tuberous sclerosis v1.5 Eleanor Williams List of related panels changed from R228 to R228; GT686; GT257; TP17
Mitochondrial disorder with complex V deficiency v3.6 Achchuthan Shanmugasundram List of related panels changed from R357 to R357; GT640; TP221
Spinal muscular atrophy type 1 rare mutation testing v1.4 Eleanor Williams List of related panels changed from R71 to R71; GT571; TP137
Mitochondrial disorder with complex IV deficiency v5.2 Achchuthan Shanmugasundram List of related panels changed from R356 to R356; GT631; TP461
Pituitary hormone deficiency v4.10 Arina Puzriakova List of related panels changed from R159 to R159; GT1249; TP259
Skeletal muscle channelopathy v3.9 Eleanor Williams List of related panels changed from R76; Myotonia congenita to Myotonia congenita; R76; GT367; TP384
Neonatal diabetes - small panel v1.7 Arina Puzriakova List of related panels changed from R143.1; Neonatal diabetes to Neonatal diabetes; R143.1; GT1019; TP437
Mitochondrial disorder with complex III deficiency v2.8 Achchuthan Shanmugasundram List of related panels changed from R355 to R355; GT891; TP272
Retinal disorders v9.5 Chr17q22 Katie Cox changed review comment from: Structural variants in the RP17 locus (Chr17q22) have been associated with retinitis pigmentosa 17, breakpoints within the genomic region spanning YPEL2 to LINC01476.
Sources: Literature; to: Structural variants in the RP17 locus (Chr17q22) have been associated with retinitis pigmentosa 17, breakpoints within the genomic region spanning YPEL2 to LINC01476.
Sources: Literature
Neonatal diabetes v6.2 Arina Puzriakova List of related panels changed from Neonatal diabetes (diagnosed less than 6 months); Neonatal diabetes diagnosed <6 months; Diabetes - neonatal onset; R143 to Neonatal diabetes (diagnosed less than 6 months); Neonatal diabetes diagnosed <6 months; Diabetes - neonatal onset; R143; GT346; TP437
Mitochondrial disorder with complex II deficiency v2.12 Achchuthan Shanmugasundram List of related panels changed from R354 to R354; GT446; TP472
Multiple endocrine neoplasia type 2 v1.4 Arina Puzriakova List of related panels changed from R218 to R218; GT1254; TP376
Multi locus imprinting disorders v2.2 Arina Puzriakova List of related panels changed from R417.2 to R417.2; GT377; TP270
Severe microcephaly v9.7 Eleanor Williams List of related panels changed from Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; R88 to Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; R88; GT370; TP54
Monogenic short stature v2.8 Arina Puzriakova List of related panels changed from R453 to R453; GT193; TP365
Mitochondrial disorder with complex I deficiency v4.2 Achchuthan Shanmugasundram List of related panels changed from R353 to R353; GT349; TP318
Retinal disorders v9.5 Chr17q22 Katie Cox Region: Chr17q22 was added
Region: Chr17q22 was added to Retinal disorders. Sources: Literature
Mode of inheritance for Region: Chr17q22 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for Region: Chr17q22 were set to PMID: 33022222
Phenotypes for Region: Chr17q22 were set to Retinitis pigmentosa
Penetrance for Region: Chr17q22 were set to Complete
Review for Region: Chr17q22 was set to GREEN
Region: Chr17q22 was marked as current diagnostic
Added comment: Structural variants in the RP17 locus (Chr17q22) have been associated with retinitis pigmentosa 17, breakpoints within the genomic region spanning YPEL2 to LINC01476.
Sources: Literature
Monogenic diabetes v3.26 Arina Puzriakova List of related panels changed from R141 to R141; GT362; TP258
Segmental or atypical neurofibromatosis type 1 testing v1.4 Eleanor Williams List of related panels changed from R376 to R376; GT1270; TP251
IPEX - Immunodysregulation Polyendocrinopathy and Enteropathy, X-Linked v1.4 Arina Puzriakova List of related panels changed from R157 to R157; GT590; TP317
Mitochondrial Complex V deficiency, TMEM70 type v1.4 Achchuthan Shanmugasundram List of related panels changed from R396 to R396; GT970; TP303
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.3 Arina Puzriakova List of related panels changed from R223 to R223; GT968; TP432
Paroxysmal central nervous system disorders v4.4 Eleanor Williams List of related panels changed from Paroxysmal neurological disorders; pain disorders and sleep disorders; R66 to Paroxysmal neurological disorders; pain disorders and sleep disorders; R66; GT801; TP74
Inherited parathyroid cancer v1.4 Arina Puzriakova List of related panels changed from R226 to R226; GT938; TP31
Tay-Sachs disease v1.4 Achchuthan Shanmugasundram List of related panels changed from R286 to R286; GT848; TP367
Hypophosphataemia or rickets v4.4 Arina Puzriakova List of related panels changed from R154 to R154; GT753; TP239
Hypogonadotropic hypogonadism (GMS) v5.3 Arina Puzriakova List of related panels changed from Hypogonadotropic hypogonadism idiopathic; R148 to Hypogonadotropic hypogonadism idiopathic; R148; GT626; TP508
Other rare neuromuscular disorders v31.113 Eleanor Williams List of related panels changed from Neuromuscular disorders; R381 to Neuromuscular disorders; R381; GT1059; TP350
Hyperthyroidism v3.7 Arina Puzriakova List of related panels changed from Resistance to thyroid hormone; R182 to Resistance to thyroid hormone; R182; GT966; TP60
Hereditary isolated diabetes insipidus v2.3 Arina Puzriakova List of related panels changed from Neuropophyseal diabetes insipidus; R440 to Neuropophyseal diabetes insipidus; R440; GT150; TP551
Neurofibromatosis type 1 (GMS) v1.5 Eleanor Williams List of related panels changed from R222 to R222; GT867; TP251
Glucokinase-related fasting hyperglycaemia v1.4 Arina Puzriakova List of related panels changed from R142 to R142; GT899; TP471
Malignant hyperthermia v1.6 Eleanor Williams List of related panels changed from R371 to R371; GT1075; TP405
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.9 Eleanor Williams List of related panels changed from Limb girdle muscular dystrophy; R82 to Limb girdle muscular dystrophy; R82; GT1037; TP111
Familial tumoral calcinosis v1.12 Arina Puzriakova List of related panels changed from R162 to R162; GT240; TP481
Hydrocephalus v5.13 Eleanor Williams List of related panels changed from Hydrocephalus; R86 to Hydrocephalus; R86; GT719; TP187
Holoprosencephaly v6.2 Eleanor Williams List of related panels changed from Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85 to Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85; GT142; TP125
Familial hypoparathyroidism v3.6 Arina Puzriakova List of related panels changed from Familial or syndromic hypoparathyroidism; R153 to Familial or syndromic hypoparathyroidism; R153; GT990; TP359
Hereditary neuropathy or pain disorder v8.5 Eleanor Williams List of related panels changed from Hereditary neuropathy NOT PMP22 copy number; Hereditary neuropathy or pain disorder - NOT PMP22 copy number; R78 to Hereditary neuropathy NOT PMP22 copy number; Hereditary neuropathy or pain disorder - NOT PMP22 copy number; R78; GT1108; TP632
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v3.9 Arina Puzriakova List of related panels changed from Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151 to Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151; GT1100; TP492
Familial dysalbuminaemic hyperthyroxinaemia v1.4 Arina Puzriakova List of related panels changed from R329 to R329; GT18; TP364
Endocrine neoplasia v3.6 Arina Puzriakova List of related panels changed from Endocrine neoplasms; R217 to Endocrine neoplasms; R217; GT127; TP59
Inherited predisposition to GIST v1.17 Ida Ertmanska List of related panels changed from R363 to R363; GT971; TP129
Differences in sex development v4.22 Arina Puzriakova List of related panels changed from R146; Disorders of sex development to Disorders of sex development; R146; GT771; TP322
Hereditary ataxia and cerebellar anomalies - childhood onset v23.5 Eleanor Williams List of related panels changed from Hereditary ataxia with onset in childhood; Cerebellar anomalies; R55; R84 to Hereditary ataxia with onset in childhood; Cerebellar anomalies; R55; R84; GT936; TP356; TP411
Inherited polyposis and early onset colorectal cancer - germline testing v4.2 Ida Ertmanska List of related panels changed from Inherited polyposis; R211 to Inherited polyposis; R211; GT1289; TP447
Congenital hypothyroidism v3.5 Arina Puzriakova List of related panels changed from Congenital hypothyroidism or thyroid agenesis; R145 to Congenital hypothyroidism or thyroid agenesis; R145; GT229; TP433
Inherited pancreatic cancer v3.4 Ida Ertmanska List of related panels changed from R367 to R367; GT297; TP108
Congenital hyperinsulinism v3.9 Arina Puzriakova List of related panels changed from Hyperinsulinism; R144 to Hyperinsulinism; R144; GT544; TP368
Inherited ovarian cancer (without breast cancer) v5.2 Ida Ertmanska List of related panels changed from Familial ovarian cancer; R207 to Familial ovarian cancer; R207; GT904; TP174
Inherited MMR deficiency (Lynch syndrome) v1.15 Ida Ertmanska List of related panels changed from R210 to R210; GT768; TP168
Inherited breast cancer and ovarian cancer v3.2 Ida Ertmanska List of related panels changed from R208 to R208; GT324; TP547
Congenital adrenal hypoplasia v5.5 Arina Puzriakova List of related panels changed from R150 to R150; GT1284; TP371
Hereditary diffuse gastric cancer v2.6 Ida Ertmanska List of related panels changed from CDH1-related cancer syndrome; R215 to CDH1-related cancer syndrome; R215; GT689; TP404
Congenital adrenal hyperplasia diagnostic test v1.4 Arina Puzriakova List of related panels changed from R180 to R180; GT724; TP41
Carney complex v1.4 Arina Puzriakova List of related panels changed from R156 to R156; GT2; TP454
Fumarate hydratase-related tumour syndromes v1.4 Ida Ertmanska List of related panels changed from R365 to R365; GT558; TP263
Calcium-sensing receptor phenotypes v1.4 Arina Puzriakova List of related panels changed from R319 to R319; GT780; TP548
Familial melanoma v2.15 Ida Ertmanska List of related panels changed from R254 to R254; GT402; TP483
Embryonal tumour of possible germline origin v1.2 Ida Ertmanska List of related panels changed from R456 to R456; GT1441; TP170
DICER1-related cancer predisposition v1.4 Ida Ertmanska List of related panels changed from R364 to R364; GT182; TP265
BAP1 associated tumour predisposition syndrome v1.4 Ida Ertmanska List of related panels changed from R422 to R422; GT648; TP372
APC associated Polyposis v1.4 Ida Ertmanska List of related panels changed from R414 to R414; GT650; TP55
Wiskott-Aldrich syndrome v1.5 Ida Ertmanska List of related panels changed from R20 to R20; GT365; TP342
Severe combined immunodeficiency with PNP deficiency v1.4 Ida Ertmanska List of related panels changed from R234 to R234; GT396; TP254
Severe combined immunodeficiency with adenosine deaminase deficiency v1.6 Ida Ertmanska List of related panels changed from R16 to R16; GT43; TP558
Smith-Lemli-Opitz syndrome v1.4 Achchuthan Shanmugasundram List of related panels changed from R270 to R270; GT659; TP201
SCID with features of gamma chain deficiency v1.4 Ida Ertmanska List of related panels changed from R235 to R235; GT572; TP388
Beckwith-Wiedemann syndrome v1.4 Arina Puzriakova List of related panels changed from R49.3 to R49.3; GT758; TP566
Primary immunodeficiency or monogenic inflammatory bowel disease v9.16 Ida Ertmanska List of related panels changed from Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; Primary immunodeficiency; R15 to Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; Primary immunodeficiency; R15; GT1295; GT837; TP223
Sitosterolaemia v1.5 Achchuthan Shanmugasundram List of related panels changed from R323 to R323; GT569; TP87
Lymphoproliferative syndrome with absent SAP expression v1.4 Ida Ertmanska List of related panels changed from R17 to R17; GT392; TP296
Hereditary angioedema types I and II v1.4 Ida Ertmanska List of related panels changed from R341 to R341; GT603; TP10
Sandhoff disease v1.4 Achchuthan Shanmugasundram List of related panels changed from R285 to R285; GT378; TP39
Haemophagocytic syndrome with absent XIAP expression v1.5 Ida Ertmanska List of related panels changed from R18 to R18; GT390; TP581
Haemophagocytic syndrome with absent perforin expression v1.5 Ida Ertmanska List of related panels changed from R232 to R232; GT553; TP366
Autoinflammatory disorders v3.10 Ida Ertmanska List of related panels changed from R413 to R413; GT1098; TP52
Phenylketonuria v1.4 Achchuthan Shanmugasundram List of related panels changed from R283 to R283; GT124; TP565
Autoimmune Polyendocrine Syndrome v1.5 Ida Ertmanska List of related panels changed from R155 to R155; GT628; TP276
Niemann-Pick disease type A or B v1.4 Achchuthan Shanmugasundram List of related panels changed from R282 to R282; GT364; TP279
Familial tumours of the nervous system v3.2 Eleanor Williams List of related panels changed from R221 to R221; GT735; TP166
Autoimmune lymphoproliferative syndrome with defective apoptosis v1.4 Ida Ertmanska List of related panels changed from R19 to R19; GT651; TP156
Niemann Pick disease type C v1.5 Achchuthan Shanmugasundram List of related panels changed from R380 to R380; GT179; TP519
Agammaglobulinaemia with absent BTK expression v1.4 Ida Ertmanska List of related panels changed from R233 to R233; GT141; TP47
Facioscapulohumeral muscular dystrophy - extended testing v1.4 Eleanor Williams List of related panels changed from R345 to R345; GT722; TP629
Neuronal ceroid lipofuscinosis type 2 v1.4 Achchuthan Shanmugasundram List of related panels changed from R271 to R271; GT1244; TP327
Duchenne or Becker muscular dystrophy v1.4 Eleanor Williams List of related panels changed from R73 to R73; GT1251; TP122
von Willebrand disease v1.5 Ida Ertmanska List of related panels changed from R121 to R121; GT470; TP14
Alstrom syndrome v1.4 Arina Puzriakova List of related panels changed from R106 to R106; GT610; TP155
Thrombophilia with a likely monogenic cause v3.2 Ida Ertmanska List of related panels changed from Thrombophilia; R97 to Thrombophilia; R97; GT116; TP120
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v1.11 Arina Puzriakova List of related panels changed from R293 to R293; GT582; TP386
Thrombocythaemia v2.2 Ida Ertmanska List of related panels changed from R406 to R406; GT1176; TP417
Neuronal ceroid lipofuscinosis v3.3 Achchuthan Shanmugasundram List of related panels changed from R231 to R231; GT310; TP210
Congenital myopathy v7.77 Eleanor Williams List of related panels changed from R81 to R81; GT988; TP240
Sickle cell, thalassaemia and other haemoglobinopathies v2.10 Ida Ertmanska List of related panels changed from R93; Thalassaemia and other haemoglobinopathies to R93; Thalassaemia and other haemoglobinopathies; GT713; TP199; TP473
Paediatric disorders v75.113 Arina Puzriakova List of related panels changed from Congenital malformation and dysmorphism syndromes - microarray and sequencing; Congenital malformation and dysmorphism syndromes; R27 to Congenital malformation and dysmorphism syndromes - microarray and sequencing; Congenital malformation and dysmorphism syndromes; R27; GT1095; TP459
Congenital myaesthenic syndrome v6.2 Eleanor Williams List of related panels changed from Congenital myaesthenia; Congenital myasthenia; R80 to Congenital myaesthenia; Congenital myasthenia; R80; GT950; TP61
Mucopolysaccharidosis type VI v1.4 Achchuthan Shanmugasundram List of related panels changed from R290 to R290; GT826; TP440
Rare anaemia v4.7 Ida Ertmanska List of related panels changed from R92 to R92; GT455; TP301
Congenital muscular dystrophy v7.22 Eleanor Williams List of related panels changed from R79 to R79; GT273; TP80
Nijmegen breakage syndrome v1.4 Ida Ertmanska List of related panels changed from R259.2 to R259.2; GT132; TP216
Mucopolysaccharidosis type IVA v1.4 Achchuthan Shanmugasundram List of related panels changed from R287 to R287; GT1119; TP385
Hypotonic infant v46.145 Arina Puzriakova List of related panels changed from Floppy infant with a likely central cause; Hypotonic infant with a likely central cause; R69 to Floppy infant with a likely central cause; Hypotonic infant with a likely central cause; R69; GT46; TP383
Childhood onset leukodystrophy v31.49 Eleanor Williams List of related panels changed from White matter disorders - childhood onset; R109 to White matter disorders - childhood onset; R109; GT207; TP419
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v3.8 Arina Puzriakova List of related panels changed from Cockayne and Xeroderma Pigmentosum-like disorders; Cockayne syndrome; Xeroderma Pigmentosum-like disorders; XP-like disorders; R227 to Cockayne and Xeroderma Pigmentosum-like disorders; Cockayne syndrome; Xeroderma Pigmentosum-like disorders; XP-like disorders; R227; GT1099; TP332
Neutropaenia consistent with ELANE mutations v1.4 Ida Ertmanska List of related panels changed from R313 to R313; GT502; TP76
Mucopolysaccharidosis type IIIB v1.4 Achchuthan Shanmugasundram List of related panels changed from R292 to R292; GT893; TP143
Monitoring for G(M)CSF escape mutations v1.4 Ida Ertmanska List of related panels changed from R338 to R338; GT188; TP539
Iron metabolism disorders - NOT common HFE mutations v4.3 Ida Ertmanska List of related panels changed from Iron metabolism disorders; R96 to Iron metabolism disorders; R96; GT715; TP630
Inherited susceptibility to acute lymphoblastoid leukaemia (ALL) v1.5 Ida Ertmanska List of related panels changed from R366 to R366; GT540; TP396
Mucopolysaccharidosis type IIIA v1.4 Achchuthan Shanmugasundram List of related panels changed from R291 to R291; GT1256; TP536
Inherited predisposition to acute myeloid leukaemia (AML) v3.8 Ida Ertmanska List of related panels changed from R347 to R347; GT204; TP464
Hereditary Erythrocytosis v3.2 Ida Ertmanska List of related panels changed from R405 to R405; GT1006; TP337
Factor XIII deficiency v1.5 Ida Ertmanska List of related panels changed from R122 to R122; GT906; TP162
Mucopolysaccharidosis type II v1.4 Achchuthan Shanmugasundram List of related panels changed from R278 to R278; GT536; TP152
Childhood onset hereditary spastic paraplegia v9.3 Eleanor Williams List of related panels changed from Hereditary spastic paraplegia - childhood onset; R61 to Hereditary spastic paraplegia - childhood onset; R61; GT34; TP579
Childhood onset dystonia, chorea or related movement disorder v8.4 Eleanor Williams List of related panels changed from Childhood onset dystonia or chorea or related movement disorder; R57 to Childhood onset dystonia or chorea or related movement disorder; R57; GT25; TP173
Factor XI deficiency v1.4 Ida Ertmanska List of related panels changed from R120 to R120; GT498; TP429
Vascular skin disorders v2.6 Arina Puzriakova List of related panels changed from R326 to R326; GT92; TP501
Cerebral vascular malformations v5.2 Eleanor Williams List of related panels changed from Cerebrovascular disorders; Vein of Galen malformation; Cerebral arteriovenous malformations; Moyamoya disease; R336 to Cerebrovascular disorders; Vein of Galen malformation; Cerebral arteriovenous malformations; Moyamoya disease; R336; GT922; TP113
Mucopolysaccharidosis type IH or S v1.4 Achchuthan Shanmugasundram List of related panels changed from R277; Mucopolysaccharidosis type IH/S to Mucopolysaccharidosis type IH/S; R277; GT1130; TP206
Factor X deficiency v1.4 Ida Ertmanska List of related panels changed from R119 to R119; GT960; TP571
Subcutaneous panniculitis T-cell lymphoma (SPTCL) v1.4 Arina Puzriakova List of related panels changed from R424 to R424; GT298; TP309
Factor VIII deficiency v1.4 Ida Ertmanska List of related panels changed from R117 to R117; GT1283; TP268
Cerebral malformation v16.7 Eleanor Williams List of related panels changed from Cerebral malformations; R87 to Cerebral malformations; R87; GT458; TP23
Segmental overgrowth disorders - Deep sequencing v5.2 Arina Puzriakova List of related panels changed from Regional overgrowth disorders; Segmental overgrowth disorders; R110 to Regional overgrowth disorders; Segmental overgrowth disorders; R110; GT1057; TP498
Factor VII deficiency v1.4 Ida Ertmanska List of related panels changed from R116 to R116; GT993; TP75
Rare genetic inflammatory skin disorders v4.20 Arina Puzriakova List of related panels changed from R332 to R332; GT1269; TP373
Pigmentary skin disorders v5.4 Arina Puzriakova List of related panels changed from R236 to R236; GT1115; TP79
Factor V deficiency v1.4 Ida Ertmanska List of related panels changed from R115 to R115; GT1159; TP369
Mucolipidosis II and III Alpha or Beta v1.4 Achchuthan Shanmugasundram List of related panels changed from R289; Mucolipidosis II and III Alpha/Beta to Mucolipidosis II and III Alpha/Beta; R289; GT835; TP556
Palmoplantar keratodermas v4.13 Arina Puzriakova List of related panels changed from R166 to R166; GT255; TP328
Factor IX deficiency v1.4 Ida Ertmanska List of related panels changed from R118 to R118; GT77; TP50
Multiple monogenic benign skin tumours v2.7 Arina Puzriakova List of related panels changed from R230 to R230; GT811; TP538
CADASIL v1.8 Eleanor Williams List of related panels changed from R337 to R337; GT1061; TP4
Factor II deficiency v1.4 Ida Ertmanska List of related panels changed from R112 to R112; GT64; TP53
Mosaic skin disorders - deep sequencing v3.28 Arina Puzriakova List of related panels changed from R327 to R327; GT878; TP169
Lysosomal storage disorder v3.10 Achchuthan Shanmugasundram List of related panels changed from R276 to R276; GT798; TP95
Cytopenia - NOT Fanconi anaemia v5.7 Ida Ertmanska List of related panels changed from R91 to R91; GT424; TP549
Incontinentia pigmenti v1.5 Arina Puzriakova List of related panels changed from R239 to R239; GT877; TP285
Ataxia telangiectasia - mutation testing v1.4 Eleanor Williams List of related panels changed from R295 to R295; GT65; TP621
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 ITGAL Boaz Palterer gene: ITGAL was added
gene: ITGAL was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ITGAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGAL were set to 41758928
Phenotypes for gene: ITGAL were set to epidermodysplasia verruciformis
Penetrance for gene: ITGAL were set to unknown
Review for gene: ITGAL was set to GREEN
Added comment: Yatim et al. described 6 subjects from 4 kindreds with biallelic variants in ITGAL presenting with EV, accounting for 10% of unexplained EV cohort. The EV cohort was therefore highly enriched in individuals homozygous for predicted deleterious ITGAL variants (10%, 4 of 40), compared with patients with other infectious diseases (0 of 25,329) and with the general population (0 of 807,162). Follows extensive ex-vivo and in vitro functional validation.
Sources: Literature
Ichthyosis and erythrokeratoderma v4.15 Arina Puzriakova List of related panels changed from R165 to R165; GT388; TP217
Confirmed Fanconi anaemia or Bloom syndrome v2.16 Ida Ertmanska List of related panels changed from R229; R258; Confirmed Fanconi anaemia or Bloom syndrome - mutation testing; Cytopenia - Fanconi breakage testing indicated to R229; R258; Confirmed Fanconi anaemia or Bloom syndrome - mutation testing; Cytopenia - Fanconi breakage testing indicated; GT566; TP191
Lysosomal acid lipase deficiency v1.4 Achchuthan Shanmugasundram List of related panels changed from R325 to R325; GT371; TP104
Epidermolysis bullosa and congenital skin fragility v2.16 Arina Puzriakova List of related panels changed from R164 to R164; GT805; TP262
Epidermodysplasia verruciformis v1.8 Arina Puzriakova List of related panels changed from R255 to R255; GT107; TP78
Combined vitamin K-dependent clotting factor deficiency v1.5 Ida Ertmanska List of related panels changed from R123 to R123; GT948; TP425
Arthrogryposis v10.11 Eleanor Williams List of related panels changed from R83 to R83; GT413; TP577
Likely inborn error of metabolism v9.12 Achchuthan Shanmugasundram List of related panels changed from Likely inborn error of metabolism - targeted testing not possible; Inborn errors of metabolism; R98 to Likely inborn error of metabolism - targeted testing not possible; Inborn errors of metabolism; R98; GT317; GT1144; TP229
Ectodermal dysplasia v5.2 Arina Puzriakova List of related panels changed from R163 to R163; GT1125; TP314
Combined factor V and VIII deficiency v1.12 Ida Ertmanska List of related panels changed from R124 to R124; GT1020; TP90
Cutaneous photosensitivity with a likely genetic cause v3.17 Arina Puzriakova List of related panels changed from R237 to R237; GT1088; TP479
Bleeding and platelet disorders v4.15 Ida Ertmanska List of related panels changed from R90 to R90; GT575; TP360
Autosomal recessive primary hypertrophic osteoarthropathy v2.2 Arina Puzriakova List of related panels changed from R167 to R167; GT1026; TP158
Wilson disease v1.4 Ida Ertmanska List of related panels changed from R172 to R172; GT1170; TP497
Unexplained death in infancy and sudden unexplained death in childhood v23.41 Arina Puzriakova List of related panels changed from R441 to R441; GT1045; TP424
Adult-onset neurological disorders v9.6 Eleanor Williams List of related panels changed from R54; R56; R60; R458; R459; R460; R461; Hereditary ataxia with onset in adulthood; Adult onset dystonia; chorea or related movement disorder; Adult onset hereditary spastic paraplegia; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy to R54; R56; R60; R458; R459; R460; R461; Hereditary ataxia with onset in adulthood; Adult onset dystonia; chorea or related movement disorder; Adult onset hereditary spastic paraplegia; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy; GT1442; TP69; TP114; TP213; TP133; TP142; TP123; TP146
Krabbe disease - Saposin A deficiency v1.4 Achchuthan Shanmugasundram List of related panels changed from R281 to R281; GT1141; TP25
Thoracic aortic aneurysm or dissection (GMS) v5.5 Arina Puzriakova List of related panels changed from Thoracic aortic aneurysm and dissection; R125 to Thoracic aortic aneurysm and dissection; R125; GT797; TP516
Krabbe disease - GALC deficiency v1.4 Achchuthan Shanmugasundram List of related panels changed from R280 to R280; GT1241; TP49
Adult onset leukodystrophy v7.3 Eleanor Williams List of related panels changed from White matter disorders - adult onset; R62 to White matter disorders - adult onset; R62; GT117; TP85
Sudden unexplained death or survivors of a cardiac event v23.17 Arina Puzriakova List of related panels changed from Molecular autopsy; Sudden cardiac death; R138 to Molecular autopsy; Sudden cardiac death; R138; GT666; TP119
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 LY9 Boaz Palterer gene: LY9 was added
gene: LY9 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: LY9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY9 were set to 40446017
Phenotypes for gene: LY9 were set to Tubercolosis
Penetrance for gene: LY9 were set to unknown
Review for gene: LY9 was set to GREEN
Added comment: Ogishi et al. described 3 subjects from 3 kindreds with homozygous LOF mutations in LY9 presenting with tuberculosis in a large TB cohort, notably no homozygous LOF was found in a large control cohort. Extensive ex-vivo and in vivo functional validation.
Sources: Literature
Short QT syndrome v3.23 Arina Puzriakova List of related panels changed from R130 to R130; GT1219; TP334
Progressive cardiac conduction disease v2.17 Arina Puzriakova List of related panels changed from R328 to R328; GT1286; TP110
Acute rhabdomyolysis v2.11 Eleanor Williams List of related panels changed from R419 to R419; GT782; TP164
GM1 Gangliosidosis and Mucopolysaccharidosis Type IVB v1.4 Achchuthan Shanmugasundram List of related panels changed from R288 to R288; GT130; TP293
Primary lymphoedema v5.2 Arina Puzriakova List of related panels changed from Lymphatic Disorders; Meiges disease; Meige disease; Milroy disease; Lymphoedema distichiasis; Lipoedema disease; R136 to Lymphatic Disorders; Meiges disease; Meige disease; Milroy disease; Lymphoedema distichiasis; Lipoedema disease; R136; GT750; TP261
Paediatric or syndromic cardiomyopathy v8.3 Arina Puzriakova List of related panels changed from Cardiomyopathies - including childhood onset; R135 to Cardiomyopathies - including childhood onset; R135; GT490; GT1273; TP159
Long QT syndrome v3.14 Arina Puzriakova List of related panels changed from Long QT; R127 to Long QT; R127; GT611; TP323
Glycogen storage disease V v1.5 Achchuthan Shanmugasundram List of related panels changed from R273 to R273; GT1054; TP1
Hypertrophic cardiomyopathy v6.3 Arina Puzriakova List of related panels changed from Hypertrophic cardiomyopathy - teen and adult; HCM; R131 to Hypertrophic cardiomyopathy - teen and adult; HCM; R131; GT1132; TP145
Thanatophoric dysplasia v1.4 Eleanor Williams List of related panels changed from R25 to R25; GT300; TP186
Generalised arterial calcification in infancy v1.5 Arina Puzriakova List of related panels changed from R384 to R384; GT62; TP423
Elastin-related phenotypes v1.4 Arina Puzriakova List of related panels changed from R140 to R140; GT249; TP521
Glycogen storage disease v2.8 Achchuthan Shanmugasundram List of related panels changed from R274 to R274; GT710; TP1
Dilated and arrhythmogenic cardiomyopathy v4.2 Arina Puzriakova List of related panels changed from Dilated cardiomyopathy - adult and teen; R132 to Dilated cardiomyopathy - adult and teen; R132; GT11; TP357
Syndromic and non syndromic craniosynostosis involving midline sutures v1.4 Eleanor Williams List of related panels changed from R416 to R416; GT896; TP562
Variegate porphyria v1.5 Ida Ertmanska List of related panels changed from R170 to R170; GT283; TP430
Catecholaminergic polymorphic VT v5.5 Arina Puzriakova List of related panels changed from Catecholaminergic Polymorphic Ventricular Tachycardia; R129 to Catecholaminergic Polymorphic Ventricular Tachycardia; R129; GT1136; TP436
Gaucher disease v1.4 Achchuthan Shanmugasundram List of related panels changed from R272 to R272; GT1172; TP160
Brugada syndrome and cardiac sodium channel disease v3.17 Arina Puzriakova List of related panels changed from Brugada syndrome; R128 to Brugada syndrome; R128; GT683; TP230
Polycystic liver disease v1.33 Ida Ertmanska List of related panels changed from Polycystic liver disease interim; R173 to Polycystic liver disease interim; R173; GT915; TP414
Fabry disease v1.4 Achchuthan Shanmugasundram List of related panels changed from R335 to R335; GT435; TP71
Pancreatitis v3.6 Ida Ertmanska List of related panels changed from R175 to R175; GT947; TP35
Barth syndrome v1.5 Arina Puzriakova List of related panels changed from R391 to R391; GT423; TP135
Paediatric pseudo-obstruction syndrome v2.7 Ida Ertmanska List of related panels changed from R438 to R438; GT201; TP38
Arrhythmogenic right ventricular cardiomyopathy v3.17 Arina Puzriakova List of related panels changed from Arrhythmogenic cardiomyopathy; R133 to Arrhythmogenic cardiomyopathy; R133; GT1053; TP338
Diagnostic testing for MCADD - Medium-chain acyl-CoA dehydrogenase deficiency - full ACADM sequencing v1.3 Achchuthan Shanmugasundram List of related panels changed from R451 to R451; GT1105; TP378
Non-acute porphyrias v1.37 Ida Ertmanska List of related panels changed from R168 to R168; GT530; TP528
Diagnostic testing for Isovaleric acidaemia v1.3 Achchuthan Shanmugasundram List of related panels changed from R450 to R450; GT1229; TP67
Intestinal failure or congenital diarrhoea v3.12 Ida Ertmanska List of related panels changed from R331; Intestinal failure to R331; Intestinal failure; GT1311; TP348
Cholestasis v4.6 Ida Ertmanska List of related panels changed from R171 to R171; GT471; TP543
Acute intermittent porphyria v2.2 Ida Ertmanska List of related panels changed from R169 to R169; GT220; TP313
Diagnostic testing for Glutaric acidaemia I v1.4 Achchuthan Shanmugasundram List of related panels changed from R449 to R449; GT374; TP407
Fetal anomalies v7.15 Ida Ertmanska List of related panels changed from R21; Fetal anomalies with a likely genetic cause; Fetal anomalies with a likely genetic cause - non urgent; R412 to R21; Fetal anomalies with a likely genetic cause; Fetal anomalies with a likely genetic cause - non urgent; R412; GT520; TP260; TP416
Cystinosis v1.4 Achchuthan Shanmugasundram List of related panels changed from R334 to R334; GT476; TP295
Familial hypercholesterolaemia (GMS) v2.6 Achchuthan Shanmugasundram List of related panels changed from Familial hypercholesterolaemia - targeted panel; R134 to Familial hypercholesterolaemia - targeted panel; R134; GT745; TP442
Severe insulin resistance and lipodystrophy syndromes v5.2 Ida Ertmanska List of related panels changed from Lipodystrophy - childhood onset; R158 to Lipodystrophy - childhood onset; R158; GT622; TP504
Familial chylomicronaemia syndrome (FCS) v3.5 Achchuthan Shanmugasundram List of related panels changed from Lipoprotein lipase deficiency; R324 to Lipoprotein lipase deficiency; R324; GT850; TP33
Severe early-onset obesity v6.2 Ida Ertmanska List of related panels changed from Significant early-onset obesity with or without other endocrine features and short stature; Significant early-onset obesity +/- other endocrine features and short stature; R149 to Significant early-onset obesity with or without other endocrine features and short stature; Significant early-onset obesity +/- other endocrine features and short stature; R149; GT630; TP139
Primary pigmented nodular adrenocortical disease v1.12 Ida Ertmanska List of related panels changed from R160 to R160; GT318; TP29
Von Hippel Lindau syndrome v1.4 Achchuthan Shanmugasundram List of related panels changed from R225 to R225; GT507; TP435
Primary hyperaldosteronism - KCNJ5 v1.4 Ida Ertmanska List of related panels changed from R344 to R344; GT176; TP410
Sarcoma of possible germline origin v1.2 Achchuthan Shanmugasundram List of related panels changed from R457 to R457; GT1443; TP148
Retinoblastoma v1.4 Achchuthan Shanmugasundram List of related panels changed from R219 to R219; GT442; TP16
PTEN Hamartoma Tumour Syndrome v1.6 Achchuthan Shanmugasundram List of related panels changed from R213; PTEN Hamartoma Tumor Syndrome to PTEN Hamartoma Tumor Syndrome; R213; GT1202; TP66
Peutz Jeghers Syndrome v1.4 Achchuthan Shanmugasundram List of related panels changed from R212 to R212; GT102; TP22
NICE approved PARP inhibitor treatment v1.3 Achchuthan Shanmugasundram List of related panels changed from R444 to R444; GT1082; TP642; TP257
Nevoid Basal Cell Carcinoma Syndrome or Gorlin syndrome v1.5 Achchuthan Shanmugasundram List of related panels changed from R214 to R214; GT761; TP534
Li Fraumeni Syndrome v1.7 Achchuthan Shanmugasundram List of related panels changed from R216 to R216; GT1087; TP51
Inherited renal cancer v1.30 Achchuthan Shanmugasundram List of related panels changed from R224 to R224; GT47; TP537
Inherited prostate cancer v1.7 Achchuthan Shanmugasundram List of related panels changed from R430 to R430; GT32; TP175
Monogenic hearing loss v6.24 Arina Puzriakova List of related panels changed from Hearing loss; Congenital hearing impairment; Autosomal dominant deafness; Congenital hearing impairment (profound/severe); Non-syndromic hearing loss; R67 to Hearing loss; Congenital hearing impairment; Autosomal dominant deafness; Congenital hearing impairment (profound/severe); Non-syndromic hearing loss; R67; GT488; TP439
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.13 CD46 Ida Ertmanska reviewed gene: CD46: Rating: GREEN; Mode of pathogenicity: None; Publications: 17018561, 29566171; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Atypical haemolytic uraemic syndrome v3.9 CD46 Ida Ertmanska edited their review of gene: CD46: Changed rating: GREEN; Changed publications to: 14566051, 29644059, 33238263, 33224962, 34169201, 38317858, 40983966; Changed phenotypes to: {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Atypical haemolytic uraemic syndrome v3.9 CD46 Ida Ertmanska changed review comment from: PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced.

PMID: 38317858 Al Riyami et al., 2023
Patient 5 - Omani ancestry - diagnosed with aHUS, heterozygous for CD46 c.175C>T, p.Arg59* (classified Pathogenic / suscept allele) and also het for CFH c.965-6T>C (VUS).

PMID: 34169201 Ardissino et al., 2021
Study highlights low penetrance: 2/32 carriers of CD46 mutations (from 16 different families) actually developed aHUS. Two affected carriers harboured CD46 c.98-1G>C and c.286+2T>G splice variants, both classified as LP - second variant also found in 4 healthy family members. Of all 186 individuals with a complement gene abnormality, only 28 developed aHUS - not CD46 specific.

PMID: 33224962 Piras et al., 2020
Studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G was the most prevalent (13/485) and was associated with <30% penetrance.
Reported a large pedigree including a proband het for CD46 c.286+2T>G with severe aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six heterozygous relatives are unaffected. Flow cytometry showed about 50% reduction of CD46 expression on blood mononuclear cells from the het proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt - highlights complexity of aHUS, and that CD46 deficiency may not be enough to induce aHUS.

CD46 is associated with AD,AR {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922 (OMIM accessed 24th Jun 2026). The association between CD46 and semi-dominant atypical hemolytic-uremic syndrome is also classified as Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, June 2024).; to: BIALLELIC CASES:
PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced. Other modifier mutations may affect penetrance here.

PMID: 33238263 Bamhraz et al., 2020
Saudi Arabian aHUS cohort.
Patient 1 homozygous for CD46: c.736T>A (p.Phe246Ile) variant, as well as het for CFI c.540A>G (p.Glu180Glu) - both labelled VUS. Disease onset at 10yrs, complete recovery after eculizumab treatment.
Patient 5 - homozygous for CD46: c.769 C>A (p.Cys 256*) - LP, as well as heterozygous for CFI c.803 C>T (p.Ser268Leu) variant (LB). Disease onset at 2.5yrs, developed into ESRD and required a post-kidney transplant.
Patient 7 - homozygous for CD46: c.350-351dup AC (p.Glu11ThfsX17) - LP. Disease onset at 21 months. Patient responded to plasma therapy leading to full recovery.

PMID: 29644059 Khandelwal et al., 2018
Cohort of Indian children with aHUS.
Sibling pairs 2–3 and 7–8 with familial disease showed a homozygous c.286 + 2T > G splice-site mutation; in both families, the parents were consanguineous. Patient 9 had a homozygous c.104G > A, p.Cys35Tyr; his affected sibling had died before genetic evaluation. 3 unrelated families total.

PMID: 14566051 Richards et al., 2003
Family 3 - recessive aHUS, CD46 c.822T>C, p.Ser206Pro. Same mutation caused aHUS in Family 2 in a heterozygous state. Demonstrated that het patients had protein expression reduced by 50%, and it was absent in homozygotes.

MONOALLELIC:
PMID: 38317858 Al Riyami et al., 2023
Patient 5 - Omani ancestry - diagnosed with aHUS, heterozygous for CD46 c.175C>T, p.Arg59* (classified Pathogenic / suscept allele) and also het for CFH c.965-6T>C (VUS).

PMID: 34169201 Ardissino et al., 2021
Study highlights low penetrance: 2/32 carriers of CD46 mutations (from 16 different families) actually developed aHUS. Two affected carriers harboured CD46 c.98-1G>C and c.286+2T>G splice variants, both classified as LP - second variant also found in 4 healthy family members. Of all 186 individuals with a complement gene abnormality, only 28 developed aHUS - not CD46 specific.

PMID: 33224962 Piras et al., 2020
Studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G was the most prevalent (13/485) and was associated with <30% penetrance.
Reported a large pedigree including a proband het for CD46 c.286+2T>G with severe aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six het relatives are unaffected. Flow cytometry showed about 50% reduction of CD46 expression on blood mononuclear cells from the het proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt - highlights complexity of aHUS, and that CD46 deficiency may not be enough to induce aHUS.

CD46 is associated with AD,AR {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922 (OMIM accessed 24th Jun 2026). The association between CD46 and semi-dominant atypical hemolytic-uremic syndrome is also classified as Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, June 2024).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 CD46 Ida Ertmanska reviewed gene: CD46: Rating: ; Mode of pathogenicity: None; Publications: 29644059, 33238263; Phenotypes: ; Mode of inheritance: None
Atypical haemolytic uraemic syndrome v3.9 CD46 Ida Ertmanska changed review comment from: PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced.

PMID: 33224962 Piras et al., 2020
Studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G was the most prevalent (13/485) and was associated with <30% penetrance.
Reported a large pedigree including a proband het for CD46 c.286+2T>G with severe aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six heterozygous relatives are unaffected. Flow cytometry showed about 50% reduction of CD46 expression on blood mononuclear cells from the het proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt - highlights complexity of aHUS, and that CD46 deficiency may not be enough to induce aHUS.; to: PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced.

PMID: 38317858 Al Riyami et al., 2023
Patient 5 - Omani ancestry - diagnosed with aHUS, heterozygous for CD46 c.175C>T, p.Arg59* (classified Pathogenic / suscept allele) and also het for CFH c.965-6T>C (VUS).

PMID: 34169201 Ardissino et al., 2021
Study highlights low penetrance: 2/32 carriers of CD46 mutations (from 16 different families) actually developed aHUS. Two affected carriers harboured CD46 c.98-1G>C and c.286+2T>G splice variants, both classified as LP - second variant also found in 4 healthy family members. Of all 186 individuals with a complement gene abnormality, only 28 developed aHUS - not CD46 specific.

PMID: 33224962 Piras et al., 2020
Studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G was the most prevalent (13/485) and was associated with <30% penetrance.
Reported a large pedigree including a proband het for CD46 c.286+2T>G with severe aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six heterozygous relatives are unaffected. Flow cytometry showed about 50% reduction of CD46 expression on blood mononuclear cells from the het proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt - highlights complexity of aHUS, and that CD46 deficiency may not be enough to induce aHUS.

CD46 is associated with AD,AR {Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922 (OMIM accessed 24th Jun 2026). The association between CD46 and semi-dominant atypical hemolytic-uremic syndrome is also classified as Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, June 2024).
Atypical haemolytic uraemic syndrome v3.9 CD46 Ida Ertmanska changed review comment from: PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced.

PMID: 33224962 Piras et al., 2020
Studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G RV was the most prevalent (13/485) and was associated with <30% penetrance.
Reported a large pedigree including a proband het for CD46 c.286+2T>G with severe aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six heterozygous relatives are unaffected. Flow cytometry showed about 50% reduction of CD46 expression on blood mononuclear cells from the het proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt - highlights complexity of aHUS, and that CD46 deficiency may not be enough to induce aHUS.; to: PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced.

PMID: 33224962 Piras et al., 2020
Studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G was the most prevalent (13/485) and was associated with <30% penetrance.
Reported a large pedigree including a proband het for CD46 c.286+2T>G with severe aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six heterozygous relatives are unaffected. Flow cytometry showed about 50% reduction of CD46 expression on blood mononuclear cells from the het proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt - highlights complexity of aHUS, and that CD46 deficiency may not be enough to induce aHUS.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 SIT1 Boaz Palterer gene: SIT1 was added
gene: SIT1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: SIT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SIT1 were set to 42128181
Phenotypes for gene: SIT1 were set to Combined immunodeficiency; Hodgkin lymphoma; Abnormal T cell physiology; Impaired CD8+ T cell cytotoxicity
Penetrance for gene: SIT1 were set to unknown
Review for gene: SIT1 was set to RED
Added comment: Pu Chen et al. described 1 patient from 1 kindred, harboring homozygous mutations in the SIT1 gene. They presented with combined immune deficiency and recurrent Hodgkin lymphoma. The underlying mechanism and phenotype were validated ex vivo using patient-derived lymphocytes and in vitro using CRISPR-Cas9-mediated SIT1 knockout T cells from healthy donors, demonstrating skewed T cell subsets, increased activation and proliferation, impaired CD8+ cytotoxicity, and defective immune synapse maturation with vesicle accumulation upon T cell receptor stimulation. The phenotype was successfully recreated with complete knockout models.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 CFH Achchuthan Shanmugasundram Tag Q2_26_expert_review tag was added to gene: CFH.
Atypical haemolytic uraemic syndrome v3.9 CD46 Ida Ertmanska reviewed gene: CD46: Rating: ; Mode of pathogenicity: None; Publications: 33224962, 40983966; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 CFB Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated families reported where individuals harbouring biallelic CFB variants presented with immunodeficiency - particularly recurrent meningococcal and pneumococcal infections. Individuals heterozygous for CFB variants present with aHUS / C3G renal disease, rather than PID. Hence, this gene can be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, with mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are now 3 unrelated families reported where individuals harbouring biallelic CFB variants presented with immunodeficiency - particularly recurrent meningococcal and pneumococcal infections. Individuals heterozygous for GoF CFB variants present with aHUS / C3G renal disease (PMID: 17182750), rather than PID. Hence, this gene can be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, with mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 CFB Ida Ertmanska Classified gene: CFB as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 CFB Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated families reported where individuals harbouring biallelic CFB variants presented with immunodeficiency - particularly recurrent meningococcal and pneumococcal infections. Individuals heterozygous for CFB variants present with aHUS / C3G renal disease, rather than PID. Hence, this gene can be promoted to Green on Primary immunodeficiency or monogenic inflammatory bowel disease, with mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.15 CFB Ida Ertmanska Gene: cfb has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.14 CFB Ida Ertmanska Phenotypes for gene: CFB were changed from Complement factor B deficiency, 615561; Atypical Hemolytic-uremic syndrome; Infections with encapsulated organisms; Complement Deficiencies; Susceptibility to atypical haemolytic uraemic syndrome 4 (AD); complement factor B deficiency (AR) to Complement factor B deficiency, OMIM:615561; {Hemolytic uremic syndrome, atypical, susceptibility to, 4}, OMIM:612924
Primary immunodeficiency or monogenic inflammatory bowel disease v9.13 CFB Ida Ertmanska Publications for gene: CFB were set to 24152280; 4109808
Primary immunodeficiency or monogenic inflammatory bowel disease v9.12 CFB Ida Ertmanska Mode of inheritance for gene: CFB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.11 CFB Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CFB.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.11 CFB Ida Ertmanska reviewed gene: CFB: Rating: GREEN; Mode of pathogenicity: None; Publications: 24152280, 33165708, 41663882; Phenotypes: Complement factor B deficiency, OMIM:615561, {Hemolytic uremic syndrome, atypical, susceptibility to, 4}, OMIM:612924; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.11 CFH Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have recurrent (meningococcal) infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene is tagged for demotion from Green to Amber, with expert review also requested.; to: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have recurrent (meningococcal) infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene is tagged for demotion from Green to Amber, with expert review also requested.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.11 CFH Ida Ertmanska changed review comment from: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have meningococcal infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene is tagged for demotion from Green to Amber, with expert review also requested.; to: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have recurrent (meningococcal) infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene is tagged for demotion from Green to Amber, with expert review also requested.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.11 CFH Ida Ertmanska commented on gene: CFH: Comment on list classification: There are numerous patients reported with both monoallelic and biallelic CFH variants and renal disease (aHUS, MPGN). However, there is little evidence of patients with FH deficiency having primary immunodeficiency. Of more than 30 patients summarised below, only two were reported to have meningococcal infections - this is posed to be secondary to acquired deficiency of other complements (PMID: 14978182). Hence, this gene is tagged for demotion from Green to Amber, with expert review also requested.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.11 CFH Ida Ertmanska Phenotypes for gene: CFH were changed from Complement factor H deficiency, 609814; Infections, disseminated neisserial infections, atypical Hemolytic-uremic syndrome, preeclampsia, dense deposit disease; Complement Deficiencies to Complement factor H deficiency, OMIM:609814; {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400
Primary immunodeficiency or monogenic inflammatory bowel disease v9.10 CFH Ida Ertmanska Publications for gene: CFH were set to 7742208; 9312129; 10803850; 2966809; 14978182; 16612335; 1701856; 24722444
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 CFH Ida Ertmanska Tag Q2_26_demote_amber tag was added to gene: CFH.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 CFH Ida Ertmanska edited their review of gene: CFH: Changed rating: AMBER; Changed publications to: 12091909, 14978182, 31440263, 32064578, 35084692, 36211394
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 CFH Ida Ertmanska changed review comment from: PMID: 36211394 Gouda et al., 2022
Egyptian cohort of 40 patients with LN, lupus nephritis (23) or PIGN, post-infectious glomerulonephritis (17), tested for genetic variants in CFH and CD46 genes. VUS CFH:p.F614S variant was found in 28 (70%) of patients: 17 (74%) of LN patients, and 11 (65%) of PIGN patients. 3 Pathogenic CFH mutations were detected in a heterozygous state in LN patients: c.514C>T (p.Q172*), c.2103G>A (p.W701*), and c.3288G>A (p.W1096*).

PMID: 35084692 Shears et al., 2022
Forty patients, median age 19 (range 3–62) years, were identified with terminal complement deficiencies. 2 White European patients had CFH variants and meningococcal infections and septicemia; 1 patient had non-meningococcal sepsis. Both were homozygous for CFH c.2T>C, p.Met1? variant (related?).

PMID: 32064578 Brodszki et al., 2020
"Complement deficiencies account for ~5% of PIDs." <30 patients reported with CFH variants according to the lit review.

PMID: 31440263 Sissy et al., 2019
13 patients reported with 7 different homozygous CFH variants and Factor H deficiency (primarily resulting in severe or multiple infections—mainly meningococcal infections—or severe autoimmune diseases). However, in this cohort, all 13 patients with CFH variants presented with kidney disease and no recurrent infections.

PMID: 14978182 Dragon-Durey et al., 2004
Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS.

CFH is associated with AD,AR Complement factor H deficiency, OMIM:609814 and AD, AR {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400, among others (OMIM accessed 22nd Jun 2026). The association between CFH and semidominant atypical hemolytic-uremic syndrome is Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, July 2023); CFH-related AR C3 glomerulonephritis is also Definitive (Complement-Mediated Kidney Diseases GCEP, Feb 2024).; to: PMID: 36211394 Gouda et al., 2022
Egyptian cohort of 40 patients with LN, lupus nephritis (23) or PIGN, post-infectious glomerulonephritis (17), tested for genetic variants in CFH and CD46 genes. VUS CFH:p.F614S variant was found in 28 (70%) of patients: 17 (74%) of LN patients, and 11 (65%) of PIGN patients. 3 Pathogenic CFH mutations were detected in a heterozygous state in LN patients: c.514C>T (p.Q172*), c.2103G>A (p.W701*), and c.3288G>A (p.W1096*).

PMID: 35084692 Shears et al., 2022
Forty patients, median age 19 (range 3–62) years, were identified with terminal complement deficiencies. 2 White European patients had CFH variants and meningococcal infections and septicemia; 1 patient had non-meningococcal sepsis. Both were homozygous for CFH c.2T>C, p.Met1? variant (related?).

PMID: 32064578 Brodszki et al., 2020
"Complement deficiencies account for ~5% of PIDs." <30 patients reported with CFH variants according to the lit review.

PMID: 31440263 Sissy et al., 2019
13 patients reported with 7 different homozygous CFH variants and Factor H deficiency (primarily resulting in severe or multiple infections—mainly meningococcal infections—or severe autoimmune diseases). However, in this cohort, all 13 patients with CFH variants presented with kidney disease and no recurrent infections.

PMID: 14978182 Dragon-Durey et al., 2004
Reported are 16 FH-deficient patients. Among six patients with homozygous deficiency, four presented with membranoproliferative glomerulonephritis, and two with atypical hemolytic uremic syndrome (HUS). The ten other patients had heterozygous FH deficiency and developed atypical HUS. No mention of recurring infections in these patients - authors pose that previously reported susceptibility to meningococcal disease is secondary to acquired C3 or C5-C9 deficiencies.

Functional:
PMID: 12091909 Pickering et al., 2002 - mouse Cfh knockout caused membranoproliferative glomerulonephritis, seen at 8 months old.

CFH is associated with AD,AR Complement factor H deficiency, OMIM:609814 and AD, AR {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400, among others (OMIM accessed 22nd Jun 2026). The association between CFH and semidominant atypical hemolytic-uremic syndrome is Definitive in ClinGen (Complement-Mediated Kidney Diseases GCEP, July 2023); CFH-related AR C3 glomerulonephritis is also Definitive (Complement-Mediated Kidney Diseases GCEP, Feb 2024).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 CFH Ida Ertmanska edited their review of gene: CFH: Changed rating: GREEN; Changed publications to: 14978182, 31440263, 32064578, 35084692, 36211394; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 CFH Ida Ertmanska reviewed gene: CFH: Rating: ; Mode of pathogenicity: None; Publications: 31440263, 35084692, 36211394; Phenotypes: Complement factor H deficiency, OMIM:609814, {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400; Mode of inheritance: None
Fetal anomalies v7.14 ABCC6 Arina Puzriakova Phenotypes for gene: ABCC6 were changed from ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2 to Arterial calcification, generalized, of infancy, 2, OMIM:614473
DDG2P v7.2 ABCC6 Arina Puzriakova Phenotypes for gene: ABCC6 were changed from ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2 614473 to Arterial calcification, generalized, of infancy, 2, OMIM:614473
Palmoplantar keratodermas v4.12 AAGAB Arina Puzriakova Phenotypes for gene: AAGAB were changed from Palmoplantar keratoderma to Keratoderma, palmoplantar, punctate type IA, OMIM:148600
Severe microcephaly v9.6 MED17 Ida Ertmanska Classified gene: MED17 as Amber List (moderate evidence)
Severe microcephaly v9.6 MED17 Ida Ertmanska Added comment: Comment on list classification: There are 4 unrelated families (Jewish families with potential founder variant counted as one) where individuals had progressive microcephaly and harboured biallelic MED17 variants. However, only the Jewish patients in PMID 20950787 met the severity criteria of HC more severe than -3SD or <0.4 percentile. Other cases were -2SD for age, and 'under 3rd percentile'. Hence, this gene can only be rated Amber until more evidence emerges.
Severe microcephaly v9.6 MED17 Ida Ertmanska Gene: med17 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v9.5 MED17 Ida Ertmanska Publications for gene: MED17 were set to 20950787; 30345598; 26004231; 33756211
Severe microcephaly v9.4 MED17 Ida Ertmanska reviewed gene: MED17: Rating: AMBER; Mode of pathogenicity: None; Publications: 20950787, 26004231, 30345598, 36508181; Phenotypes: Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.13 MED17 Ida Ertmanska edited their review of gene: MED17: Changed publications to: 20950787, 26004231, 30345598, 36508181
Early onset or syndromic epilepsy v9.13 MED17 Ida Ertmanska changed review comment from: PMID: 30345598 Agostini et al., 2018
Report of two siblings presenting with failure to thrive in early years, progressive microcephaly, moderate intellectual disability, developmental delay, ataxic gait and seizures with an identical EEG pattern, and minimal cerebellar atrophy. Both sibs were comp het for MED17: p.Glu16fs and p.Gly253Arg (confirmed in trans).

PMID: 36508181 Rafiullah et al., 2022
Consanguineous family with individuals presenting with severe ID, seizure, and progressive microcephaly. Magnetic resonance imaging (MRI) of the brain showed mild brain atrophy and myelination defect. WES detected homozygous MED17 variant NM_004268.5_c.871T>C; p.Trp291Gly - confirmed het in unaffected parents and sibs.

MED17 is associated with AR Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM:613668 (OMIM accessed 22nd Jun 2026).; to: PMID 20950787 Kaufmann et al., 2010
Homozygous variant p.L371P was identified in 9 patients from 4 Caucasus Jewish families. Five infants from four unrelated families presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect.

PMID: 26004231 Hirabayashi, Saitsu, & Matsumoto, 2016
2 sibs with nystagmus and sudden opistotonic posturing from the early infancy, developmental delay and marked choreiform movements with hypotonia in the childhood. The brother had a mild postnatal microcephaly. Brain MRI of the sister showed mild delay of myelination, dilated anterior horn and mild cerebellar atrophy. WES revealed comp het MED17 mutations in both: c.1013-5A>G, p. Ser338Asnfs*15 and c.1484T>G, p.Leu495Trp (in trans).

PMID: 30345598 Agostini et al., 2018
Report of two siblings presenting with failure to thrive in early years, progressive microcephaly, moderate intellectual disability, developmental delay, ataxic gait and seizures with an identical EEG pattern, and minimal cerebellar atrophy. Both sibs were comp het for MED17: p.Glu16fs and p.Gly253Arg (confirmed in trans).

PMID: 36508181 Rafiullah et al., 2022
Consanguineous family with individuals presenting with severe ID, seizure, and progressive microcephaly. Magnetic resonance imaging (MRI) of the brain showed mild brain atrophy and myelination defect. WES detected homozygous MED17 variant NM_004268.5_c.871T>C; p.Trp291Gly - confirmed het in unaffected parents and sibs.

MED17 is associated with AR Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM:613668 (OMIM accessed 22nd Jun 2026).
Early onset or syndromic epilepsy v9.13 MED17 Ida Ertmanska Classified gene: MED17 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.13 MED17 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated families where affected individuals harboured biallelic MED17 variants and presented with seizures (among other syndromic symptoms). Based on available evidence, this gene can be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.13 MED17 Ida Ertmanska Gene: med17 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.12 MED17 Ida Ertmanska Publications for gene: MED17 were set to 26004231; 20950787; 30345598
Early onset or syndromic epilepsy v9.11 MED17 Ida Ertmanska Tag watchlist was removed from gene: MED17.
Tag Q2_26_promote_green tag was added to gene: MED17.
Early onset or syndromic epilepsy v9.11 MED17 Ida Ertmanska reviewed gene: MED17: Rating: GREEN; Mode of pathogenicity: None; Publications: 30345598, 36508181; Phenotypes: Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial melanoma v2.14 MITF Achchuthan Shanmugasundram Classified gene: MITF as Amber List (moderate evidence)
Familial melanoma v2.14 MITF Achchuthan Shanmugasundram Added comment: Comment on list classification: There is emerging evidence for significant enrichment of germline p.Glu318Lys variant from MITF gene in melanoma patients in comparison to population control. However, there are no other variants from this gene has been associated with risk of melanoma. This gene has been rated amber with current evidence.
Familial melanoma v2.14 MITF Achchuthan Shanmugasundram Gene: mitf has been classified as Amber List (Moderate Evidence).
Familial melanoma v2.13 MITF Achchuthan Shanmugasundram Phenotypes for gene: MITF were changed from Mucosal melanoma to {Melanoma, cutaneous malignant, susceptibility to, 8}, OMIM:614456; melanoma, cutaneous malignant, susceptibility to, 8, MONDO:0013759
Familial melanoma v2.12 MITF Achchuthan Shanmugasundram Publications for gene: MITF were set to PMID: 42177185
Familial melanoma v2.11 MITF Achchuthan Shanmugasundram Mode of inheritance for gene: MITF was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial melanoma v2.10 MITF Achchuthan Shanmugasundram changed review comment from: PMID:22012259 (2011) reported the presence of higher than five-fold increased risk of developing melanoma, renal cell carcinoma or both cancers in individuals with germline missense substitution in MITF gene (p.Glu318Lys), when compared with controls.

PMID: 22080950 (2011) reported the whole-genome sequencing of probands from several melanoma families, of which one individual was identified with p.Glu318Lys variant in MITF gene. The MITF variant allele was found in 3/7 melanoma cases assessed in this family, consistent with it being a medium-penetrance melanoma risk variant. This variant was significantly associated with melanoma in a large Australian case-control sample and in an independent case-control sample from the UK. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets.

PMID:42177185 (2026) reported a study of 346 mucosal melanoma patients, of which germline pathogenic variant in MITF (p.Glu318Lys) was identified in six patients, which was a significant enrichment compared to population control rates.

This gene has been associated with relevant susceptibility phenotype in OMIM (MIM #614456) and OMIm record was last accessed 19 June 2026.; to: PMID:22012259 (2011) reported the presence of higher than five-fold increased risk of developing melanoma, renal cell carcinoma or both cancers in individuals with germline missense substitution in MITF gene (p.Glu318Lys), when compared with controls.

PMID: 22080950 (2011) reported the whole-genome sequencing of probands from several melanoma families, of which one individual was identified with p.Glu318Lys variant in MITF gene. The MITF variant allele was found in 3/7 melanoma cases assessed in this family, consistent with it being a medium-penetrance melanoma risk variant. This variant was significantly associated with melanoma in a large Australian case-control sample and in an independent case-control sample from the UK. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets.

PMID:42177185 (2026) reported a study of 346 mucosal melanoma patients, of which germline pathogenic variant in MITF (p.Glu318Lys) was identified in six patients, which was a significant enrichment compared to population control rates.

This gene has been associated with relevant susceptibility phenotype in OMIM (MIM #614456) and OMIM record was last accessed 19 June 2026. This gene is included in Cancer panel with 'limited' rating in Gene2Phenotype.
Familial melanoma v2.10 MITF Achchuthan Shanmugasundram changed review comment from: PMID:22012259 (2011) reported the presence of higher than five-fold increased risk of developing melanoma, renal cell carcinoma or both cancers in individuals with germline missense substitution in MITF gene (p.Glu318Lys), when compared with controls.

PMID: 22080950 (2011) reported the whole-genome sequencing of probands from several melanoma families, of which one individual was identified with p.Glu318Lys variant in MITF gene. The MITF variant allele was found in 3/7 melanoma cases assessed in this family, consistent with it being a medium-penetrance melanoma risk variant. This variant was significantly associated with melanoma in a large Australian case-control sample and in an independent case-control sample from the UK. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. ; to: PMID:22012259 (2011) reported the presence of higher than five-fold increased risk of developing melanoma, renal cell carcinoma or both cancers in individuals with germline missense substitution in MITF gene (p.Glu318Lys), when compared with controls.

PMID: 22080950 (2011) reported the whole-genome sequencing of probands from several melanoma families, of which one individual was identified with p.Glu318Lys variant in MITF gene. The MITF variant allele was found in 3/7 melanoma cases assessed in this family, consistent with it being a medium-penetrance melanoma risk variant. This variant was significantly associated with melanoma in a large Australian case-control sample and in an independent case-control sample from the UK. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets.

PMID:42177185 (2026) reported a study of 346 mucosal melanoma patients, of which germline pathogenic variant in MITF (p.Glu318Lys) was identified in six patients, which was a significant enrichment compared to population control rates.

This gene has been associated with relevant susceptibility phenotype in OMIM (MIM #614456) and OMIm record was last accessed 19 June 2026.
Familial melanoma v2.10 MITF Achchuthan Shanmugasundram edited their review of gene: MITF: Changed publications to: 22012259, 22080950, 42177185
Familial melanoma v2.10 MITF Achchuthan Shanmugasundram changed review comment from: PMID:22012259 (2011) reported the presence of higher than five-fold increased risk of developing melanoma, renal cell carcinoma or both cancers in individuals with germline missense substitution in MITF gene (p.Glu318Lys), when compared with controls.

PMID: 22080950 (2011) reported the whole-genome sequencing of probands from several melanoma families, of which one individual was identified with p.Glu318Lys variant in MITF gene.; to: PMID:22012259 (2011) reported the presence of higher than five-fold increased risk of developing melanoma, renal cell carcinoma or both cancers in individuals with germline missense substitution in MITF gene (p.Glu318Lys), when compared with controls.

PMID: 22080950 (2011) reported the whole-genome sequencing of probands from several melanoma families, of which one individual was identified with p.Glu318Lys variant in MITF gene. The MITF variant allele was found in 3/7 melanoma cases assessed in this family, consistent with it being a medium-penetrance melanoma risk variant. This variant was significantly associated with melanoma in a large Australian case-control sample and in an independent case-control sample from the UK. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets.
Familial melanoma v2.10 MITF Achchuthan Shanmugasundram reviewed gene: MITF: Rating: AMBER; Mode of pathogenicity: None; Publications: 22012259, 22080950; Phenotypes: {Melanoma, cutaneous malignant, susceptibility to, 8}, OMIM:614456, melanoma, cutaneous malignant, susceptibility to, 8, MONDO:0013759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v9.4 VPS51 Ida Ertmanska edited their review of gene: VPS51: Changed rating: AMBER
Severe microcephaly v9.4 VPS51 Ida Ertmanska Classified gene: VPS51 as Amber List (moderate evidence)
Severe microcephaly v9.4 VPS51 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals with biallelic VPS51 variants and microcephaly. While microcephaly was a consistent feature in all cases, the severity was not stated, and intellectual disability is more likely to be the main Clinical Indication for these patients (now tagged for promotion). Hence, VPS51 should remain Amber on Severe microcephaly.
Severe microcephaly v9.4 VPS51 Ida Ertmanska Gene: vps51 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v9.3 VPS51 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: VPS51.
Severe microcephaly v9.3 VPS51 Ida Ertmanska Deleted their comment
Congenital myopathy v7.76 TNPO3 Achchuthan Shanmugasundram Classified gene: TNPO3 as Amber List (moderate evidence)
Congenital myopathy v7.76 TNPO3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated families with congenital/ early-onset LGMD/ myopathy. However, only one patient from the large Spanish kindred was reported with myopathy before 5 years of age. Hence, this gene can only be rated amber with the current evidence. The 'watchlist' tag has been added to review this gene in light of any new evidence.
Congenital myopathy v7.76 TNPO3 Achchuthan Shanmugasundram Gene: tnpo3 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.75 TNPO3 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: TNPO3.
Congenital myopathy v7.75 TNPO3 Achchuthan Shanmugasundram changed review comment from: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.

PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro).

PMID:31071488 (2019) reported two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones and presented with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC (p.Arg923AspfsTer17) variant in TNPO3, which was also identified in the affected son by Sanger sequencing; the unaffected son did not have the variant.

PMID:31192305 (2019) reported the identification of a novel heterozygous variant c.2757delC (p.Arg920Glyfs*20) in TNPO3 gene in a three-generation Swedish family with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal dominant 2 in OMIM (MIM #608423, last accessed 19 June 2026). It is also classified as a 'Definitive' disease association by Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:008206).; to: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.

PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro).

PMID:31071488 (2019) reported two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones and presented with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC (p.Arg923AspfsTer17) variant in TNPO3, which was also identified in the affected son by Sanger sequencing; the unaffected son did not have the variant. It appears that PMID:31217819 describes the same Hungarian family form the descriptions.

PMID:31192305 (2019) reported the identification of a novel heterozygous variant c.2757delC (p.Arg920Glyfs*20) in TNPO3 gene in a three-generation Swedish family with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal dominant 2 in OMIM (MIM #608423, last accessed 19 June 2026). It is also classified as a 'Definitive' disease association by Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:008206).
Congenital myopathy v7.75 TNPO3 Achchuthan Shanmugasundram Phenotypes for gene: TNPO3 were changed from to Muscular dystrophy, limb-girdle, autosomal dominant 2, OMIM:608423; autosomal dominant limb-girdle muscular dystrophy type 1F, MONDO:0012034
Congenital myopathy v7.74 TNPO3 Achchuthan Shanmugasundram Publications for gene: TNPO3 were set to
Congenital myopathy v7.73 TNPO3 Achchuthan Shanmugasundram changed review comment from: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.

PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro).

PMID:31071488 (2019) reported two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones and presented with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC (p.Arg923AspfsTer17) variant in TNPO3, which was also identified in the affected son by Sanger sequencing; the unaffected son did not have the variant.

PMID:31192305 (2019) reported the identification of a novel heterozygous variant c.2757delC (p.Arg920Glyfs*20) in TNPO3 gene in a three-generation Swedish family with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness.


This gene has been associated with Muscular dystrophy, limb-girdle, autosomal dominant 2 in OMIM (MIM #608423, last accessed 19 June 2026). It is also classified as a 'Definitive' disease association by Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:008206).; to: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.

PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro).

PMID:31071488 (2019) reported two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones and presented with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC (p.Arg923AspfsTer17) variant in TNPO3, which was also identified in the affected son by Sanger sequencing; the unaffected son did not have the variant.

PMID:31192305 (2019) reported the identification of a novel heterozygous variant c.2757delC (p.Arg920Glyfs*20) in TNPO3 gene in a three-generation Swedish family with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal dominant 2 in OMIM (MIM #608423, last accessed 19 June 2026). It is also classified as a 'Definitive' disease association by Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:008206).
Congenital myopathy v7.73 TNPO3 Achchuthan Shanmugasundram changed review comment from: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.

PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro).

PMID:31192305 (2019) ; to: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.

PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro).

PMID:31071488 (2019) reported two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones and presented with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC (p.Arg923AspfsTer17) variant in TNPO3, which was also identified in the affected son by Sanger sequencing; the unaffected son did not have the variant.

PMID:31192305 (2019) reported the identification of a novel heterozygous variant c.2757delC (p.Arg920Glyfs*20) in TNPO3 gene in a three-generation Swedish family with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness.


This gene has been associated with Muscular dystrophy, limb-girdle, autosomal dominant 2 in OMIM (MIM #608423, last accessed 19 June 2026). It is also classified as a 'Definitive' disease association by Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:008206).
Congenital muscular dystrophy v7.21 MCOLN1 Eleanor Williams Classified gene: MCOLN1 as Red List (low evidence)
Congenital muscular dystrophy v7.21 MCOLN1 Eleanor Williams Added comment: Comment on list classification: Assigned red rating as the phenotype is suggestive of a muscle myopathy and is not confirmed dystrophy.
Congenital muscular dystrophy v7.21 MCOLN1 Eleanor Williams Gene: mcoln1 has been classified as Red List (Low Evidence).
Congenital muscular dystrophy v7.20 MCOLN1 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 18th June 2026
Congenital muscular dystrophy v7.20 MCOLN1 Eleanor Williams Phenotypes for gene: MCOLN1 were changed from Mucolipidosis IV, OMIM:252650; mucolipidosis type IV, MONDO:0009653 to Mucolipidosis IV, OMIM:252650; mucolipidosis type IV, MONDO:0009653
Congenital muscular dystrophy v7.19 MCOLN1 Eleanor Williams Publications for gene: MCOLN1 were set to 33454187
Congenital muscular dystrophy v7.18 MCOLN1 Eleanor Williams changed review comment from: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248)                                                                                                          

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap.

; to: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248)                                                                                                          

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap.

Two other publications report cases with elevated creatine kinase in patients with homozygous variants in MCOLN1 and a myopathy, or suspected myopathy phenotype PMID:32604955 and PMID:42037965. Muscular dystrophy not mentioned in these cases.
Congenital myopathy v7.73 MCOLN1 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 18th June 2026
Congenital myopathy v7.73 MCOLN1 Eleanor Williams Phenotypes for gene: MCOLN1 were changed from to Mucolipidosis IV, OMIM:252650; mucolipidosis type IV, MONDO:0009653
Congenital myopathy v7.72 MCOLN1 Eleanor Williams Publications for gene: MCOLN1 were set to
Congenital myopathy v7.71 MCOLN1 Eleanor Williams Classified gene: MCOLN1 as Amber List (moderate evidence)
Congenital myopathy v7.71 MCOLN1 Eleanor Williams Added comment: Comment on list classification: Rating amber based on 1 case with a confirmed myopathy and 2 further cases with elevated creatine kinase and myopathy features.
Congenital myopathy v7.71 MCOLN1 Eleanor Williams Gene: mcoln1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.70 MCOLN1 Eleanor Williams edited their review of gene: MCOLN1: Changed rating: AMBER
Congenital myopathy v7.70 MCOLN1 Eleanor Williams changed review comment from: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248)

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap

Other publications that mention a myopathy phenotype in ML4 patients:

PMID: 32604955 Jezela-Stanek et al 2020
Report 2 Pakistani patients with adult onset myopathy both with homozygous MCOLN1 c.[1256G>C];p.(Arg419Pro), elevated creatine kinase and myopathy (no biopsy).; to: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248)

1 case ( Zambon et al 2021) reported of a young child with ML4 and elevated creatine kinase, a myopathy confirmed by electromyography and a homogyzous truncating variant in MCOLN1. 2 other cases with elevated creatine kinase reported.

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap

Other publications that mention a myopathy phenotype in ML4 patients:

PMID:32604955 Jezela-Stanek et al 2020
Report 2 Pakistani patients both with homozygous MCOLN1 c.[1256G>C];p.(Arg419Pro), elevated creatine kinase and myopathy (no biopsy reported) as part of their clinical features. One with congenital myopathy, other with no age of onset given but text suggests adult onset. Unclear if related or not.

PMID:42037965 Alsahlawi et al 2026
10-year-old boy from Bahrain with ML4 who presented with global developmental delay, spastic quadriparesis, severe visual impairment, gastrointestinal manifestations, and persistent elevation of creatine kinase (CK) suggestive of potential secondary myopathic involvement. No muscle biopsy reported. CK level first measured above normal at 1 year 3 months. WES identified a homozygous MCOLN1 variant (c.1336G>A; p.Val446Met). Parents were both heterozygous.
Congenital myopathy v7.70 TNPO3 Achchuthan Shanmugasundram changed review comment from: PMIDs: 23667635 & 23543484 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.; to: PMIDs: 23543484 & 23667635 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy (LGMD) and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion in TNPO3 gene (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.

PMID:23667635 (2013) reported an additional sporadic case of an Italian female patient with young adult-onset LGMD phenotype and proximal weakness and had dystrophic biopsy with mitochondrial abnormalities (ragged-red fibres, COX-negative fibres).This patient was identified with a heterozygous variant in TNPO3 gene (c.2453G>A; p.Arg818Pro).

PMID:31192305 (2019)
Congenital myopathy v7.70 CCDC78 Arina Puzriakova Phenotypes for gene: CCDC78 were changed from centronuclear myopathy-4, OMIM:614807; Centronuclear myopathy 4, MONDO:0013890 to Centronuclear myopathy 4, OMIM:614807; Centronuclear myopathy 4, MONDO:0013890
Congenital myopathy v7.69 CACNA1H Arina Puzriakova Publications for gene: CACNA1H were set to 25773295; 31070086; 41272325
Congenital myopathy v7.68 CACNA1H Arina Puzriakova Phenotypes for gene: CACNA1H were changed from to congenital amyoplasia, MONDO:0044629
Early onset or syndromic epilepsy v9.11 CACNA1H Arina Puzriakova Publications for gene: CACNA1H were set to 12891677; 32227660; 15048902
Early onset or syndromic epilepsy v9.10 CACNA1H Arina Puzriakova reviewed gene: CACNA1H: Rating: ; Mode of pathogenicity: None; Publications: 41272325; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.10 CACNA1H Arina Puzriakova Mode of inheritance for gene: CACNA1H was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital myopathy v7.67 TNPO3 Achchuthan Shanmugasundram edited their review of gene: TNPO3: Changed publications to: 23543484, 23632945, 23667635, 31071488, 31192305, 31217819
Congenital myopathy v7.67 TNPO3 Achchuthan Shanmugasundram edited their review of gene: TNPO3: Added comment: PMIDs: 23667635 & 23543484 (2013) reported a large multigenerational Spanish Pedigree with a novel form of autosomal dominant limb-girdle muscular dystrophy and they presented with limb-girdle and distal muscle weakness with variable distribution, severity, and rate of progression. A heterozygous single nucleotide deletion (c.2771del) was identified in the family via whole-genome sequencing. Detailed clinical information was provided in PMID:23632945 for 29 patients of the family, where only one patient had onset before 5 years of age.; Changed publications to: 23667635, 23543484, 23632945, 31071488, 31192305, 31217819
Congenital myopathy v7.67 TNPO3 Achchuthan Shanmugasundram reviewed gene: TNPO3: Rating: AMBER; Mode of pathogenicity: None; Publications: 23667635, 23543484, 31071488, 31192305, 31217819; Phenotypes: Muscular dystrophy, limb-girdle, autosomal dominant 2, OMIM:608423, autosomal dominant limb-girdle muscular dystrophy type 1F, MONDO:0012034; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v10.25 SF3B1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: SF3B1.
Tag Q2_26_NHS_review tag was added to gene: SF3B1.
Intellectual disability v10.25 SF3B1 Ida Ertmanska Phenotypes for gene: SF3B1 were changed from Neurodevelopmental disorder; language impairment; developmental delay; seizures; dysmorphism; congenital anomalies to Complex neurodevelopmental disorder, MONDO:0100038; Neurodevelopmental disorder; language impairment; developmental delay; seizures; dysmorphism; congenital anomalies
Intellectual disability v10.24 SF3B1 Ida Ertmanska Publications for gene: SF3B1 were set to PMID: 41577671
Intellectual disability v10.23 SF3B1 Ida Ertmanska Classified gene: SF3B1 as Amber List (moderate evidence)
Intellectual disability v10.23 SF3B1 Ida Ertmanska Added comment: Comment on list classification: There are now numerous individuals reported with monoallelic (mostly de novo) variants in SF3B1, presenting with syndromic ID/GDD. Based on available evidence, this gene can be promoted to Green at the next update.
Intellectual disability v10.23 SF3B1 Ida Ertmanska Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.22 SF3B1 Ida Ertmanska edited their review of gene: SF3B1: Changed publications to: 25363760, 28135719, 41577671
Intellectual disability v10.22 SF3B1 Ida Ertmanska changed review comment from: As reviewed by Karen Stals, Uguen et al. (PMID: 41577671, 2026) reported 26 patients with heterozygous SF3B1 variants. Most of them were confirmed to be de novo, with 3 cases where variant was inherited from a parent (2 parents with learning difficulties, and 1 asymptomatic father). Seq method: Trio or Solo WES. 3 patients had VUS variants in other genes.
"Almost all (23/26) affected individuals exhibited at least one neurodevelopmental abnormality, the most frequent being language delay (21/26). Motor delay was found in 18/24 individuals. Intellectual disability (ID) was present in 9/15 individuals, some cases being too young (8/26) to assess. The severity of ID was mainly mild to moderate, only two individuals presenting with severe ID. Seizures were reported in 13 individuals, with variable ages of onset and types." Other features: hypotonia (11 patients), spastic quadriplegia (2 patients without NDD), non-specific brain MRI anomalies (4 cases), cleft palate or high-arched palate (12 patients), heart defects (8/25), postnatal short stature (6), IUGR (5), microcephaly (7/22 assessed).

De novo missense variants in the SF3B1 gene have also been identified in three ASD probands (PMID: 25363760 De Rubeis et al., 2014 - proband with,,, PMID:25363768 Iossifov et al., 2014 - 2 probands with ASD, harbouring SF3B1 variants c.1078A>G, p.Ile360Val & c.890C>A, p.Pro297His) and two probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017).

SF3B1 is not yet associated with an NDD in OMIM, and it has not been classified in ClinGen (accessed 17th Jun 2026). The gene is Green in PanelApp Australia on 'Intellectual disability syndromic and non-syndromic' panel.; to: As reviewed by Karen Stals, Uguen et al. (PMID: 41577671, 2026) reported 26 patients with heterozygous SF3B1 variants. Most of them were confirmed to be de novo, with 3 cases where variant was inherited from a parent (2 parents with learning difficulties, and 1 asymptomatic father). Seq method: Trio or Solo WES. 3 patients had VUS variants in other genes.
"Almost all (23/26) affected individuals exhibited at least one neurodevelopmental abnormality, the most frequent being language delay (21/26). Motor delay was found in 18/24 individuals. Intellectual disability (ID) was present in 9/15 individuals, some cases being too young (8/26) to assess. The severity of ID was mainly mild to moderate, only two individuals presenting with severe ID. Seizures were reported in 13 individuals, with variable ages of onset and types." Other features: hypotonia (11 patients), spastic quadriplegia (2 patients without NDD), non-specific brain MRI anomalies (4 cases), cleft palate or high-arched palate (12 patients), heart defects (8/25), postnatal short stature (6), IUGR (5), microcephaly (7/22 assessed).

De novo missense variants in the SF3B1 gene have also been identified in ASD probands (PMID: 25363768 Iossifov et al., 2014 - 2 probands with ASD, harbouring SF3B1 variants c.1078A>G, p.Ile360Val & c.890C>A, p.Pro297His) and two probands with unspecified developmental disorders, with de novo SF3B1 variants c.1108C>T, p.Pro370Ser & c.1781G>A, p.Arg594Gln (PMID: 28135719 Deciphering Developmental Disorders Study 2017).

SF3B1 is not yet associated with an NDD in OMIM, and it has not been classified in ClinGen (accessed 17th Jun 2026). The gene is Green in PanelApp Australia on 'Intellectual disability syndromic and non-syndromic' panel.
Intellectual disability v10.22 SF3B1 Ida Ertmanska edited their review of gene: SF3B1: Changed rating: GREEN; Changed phenotypes to: Complex neurodevelopmental disorder, MONDO:0100038; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v10.22 SF3B1 Ida Ertmanska reviewed gene: SF3B1: Rating: ; Mode of pathogenicity: None; Publications: 25363768, 25363760, 41577671; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 SH2B3 Boaz Palterer gene: SH2B3 was added
gene: SH2B3 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature,Expert list
Mode of inheritance for gene: SH2B3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SH2B3 were set to 37206266
Phenotypes for gene: SH2B3 were set to Myeloproliferative disorder; Autoimmunity; Hepatosplenomegaly; Thrombosis; Autoimmune thyroiditis; Autoimmune hepatitis; Global developmental delay
Penetrance for gene: SH2B3 were set to unknown
Review for gene: SH2B3 was set to RED
Added comment: Blombery et al. described 2 patients from 2 kindreds, harboring biallelic loss-of-function mutations in the SH2B3 gene. They presented with early-onset developmental delay, hepatosplenomegaly, multi-organ autoimmunity (including autoimmune thyroiditis and hepatitis), bone marrow myeloproliferation, and severe thrombotic complications. The underlying mechanism was validated ex vivo using patient-derived fibroblasts, demonstrating that upon stimulation with various cytokines (including IL-3, GH, GM-CSF, and EPO), the mutant cells exhibited significantly increased phosphorylation and hyperactivation of JAK2 and STAT5 signaling. The phenotype and mechanism were further validated in vivo using CRISPR-Cas9 engineered zebrafish animal models (sh2b3 F0 crispants). These models successfully recreated the myeloproliferative phenotype, presenting with a significantly increased number of macrophages and thrombocytes. Furthermore, rescue and treatment experiments demonstrated that administering the JAK1/2 inhibitor ruxolitinib to the mutant fish successfully intercepted and resolved the myeloproliferative defect.
Sources: Literature, Expert list
Congenital myopathy v7.67 FOXK2 Achchuthan Shanmugasundram Classified gene: FOXK2 as Amber List (moderate evidence)
Congenital myopathy v7.67 FOXK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Anna Sarkozy, there are five unrelated families and functional evidence from zebrafish and mice available in support of the association of FOXK2 with congenital myopathy. However all five reported variants are present in gnomAD 4.1.1 (one in >2,000 individuals). Hence, this gene should not be recommended for promotion to green rating with the current evidence.
Congenital myopathy v7.67 FOXK2 Achchuthan Shanmugasundram Gene: foxk2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.66 FOXK2 Achchuthan Shanmugasundram Phenotypes for gene: FOXK2 were changed from to congenital myopathy, MONDO:0019952
Congenital myopathy v7.65 FOXK2 Achchuthan Shanmugasundram Publications for gene: FOXK2 were set to
Congenital myopathy v7.64 FOXK2 Achchuthan Shanmugasundram Mode of inheritance for gene: FOXK2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.63 FOXK2 Achchuthan Shanmugasundram reviewed gene: FOXK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 40410591; Phenotypes: congenital myopathy, MONDO:0019952; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 SHARPIN Boaz Palterer gene: SHARPIN was added
gene: SHARPIN was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature,Expert list
Mode of inheritance for gene: SHARPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHARPIN were set to 38609546
Phenotypes for gene: SHARPIN were set to Autoinflammation; Immunodeficiency; Recurrent fever; Dermatitis; Recurrent infections
Penetrance for gene: SHARPIN were set to unknown
Added comment: Oda et al. described 1 patient from 1 kindred, harboring biallelic loss-of-function mutations in the SHARPIN gene. They presented with distinct clinical autoinflammatory features, recurrent fevers, and subtle immunodeficiency. The underlying mechanism was validated ex vivo using patient-derived cells, demonstrating that the absence of SHARPIN severely destabilizes the linear ubiquitin chain assembly complex (LUBAC), resulting in impaired NF-κB signaling, defective linear ubiquitination, and dysregulated TNF-mediated cell death. The phenotype and mechanism were further validated using in vivo animal models; complete knockout Sharpin-deficient mice (Sharpin cpdm) successfully recreated the severe chronic proliferative dermatitis and multi-organ autoinflammation, confirming the gene's critical role in maintaining immune homeostasis and preventing aberrant cell death.
Sources: Literature, Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 LY96 Boaz Palterer gene: LY96 was added
gene: LY96 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Expert list,Literature
Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY96 were set to 36462957
Phenotypes for gene: LY96 were set to Inflammatory bowel disease; Pneumonia; Otitis media; Abnormal inflammatory response; Recurrent bacterial infections
Penetrance for gene: LY96 were set to unknown
Review for gene: LY96 was set to RED
Added comment: Li et al. described 2 patients from 1 kindred, harboring a homozygous mutation in the LY96 gene (c.347_349delCAA). They presented with very early-onset inflammatory bowel disease, recurrent pneumonia, and otitis media. The underlying mechanism and phenotype were validated in vitro using genetically engineered induced pluripotent stem cell (iPSC)-derived macrophages. Both LY96 knockout models and the specific patient mutation knock-in models successfully recreated the immunodeficiency phenotype, demonstrating impaired activation of NF-κB and MAPK signaling, defective TLR4 endocytosis, and significantly decreased cytokine expression (e.g., IL-6, TNF, IL-10) upon challenge with lipopolysaccharide (LPS) and Gram-negative bacteria, while host defense responses to Gram-positive bacteria remained intact.
Sources: Expert list, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 PAX5 Boaz Palterer gene: PAX5 was added
gene: PAX5 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: PAX5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX5 were set to 35947077
Phenotypes for gene: PAX5 were set to hypogammaglobulinemia; reduced B cells; sensorimotor deficits; autism spectrum disorder
Penetrance for gene: PAX5 were set to unknown
Review for gene: PAX5 was set to RED
Added comment: Kaiser et al. described 1 patient from 1 kindred, harboring compound heterozygous mutations in the PAX5 gene (p.R31Q / p.E242*). They presented with early-onset recurrent infections, severe hypogammaglobulinemia, a profound reduction of peripheral B cells, severely impaired sensorimotor learning, and autism spectrum disorder (ASD).
The underlying mechanism and phenotype were extensively validated using a patient-specific in vivo mutant mouse model (Pax5R31Q/E242* and Pax5R31Q/- mice). These animal models successfully recreated both the immunological and neurological phenotypes, demonstrating an early B-cell developmental block (arrest at the pro-B to pre-B transition), reduced B cell counts in the bone marrow, aberrant cerebellar foliation, and behavioral deficits across ASD domains. Flow cytometry analysis of both the patient's peripheral blood and the murine models confirmed the severe reduction in total B cell numbers and immune arrest. Complete knockout models (Pax5E242*/E242*) demonstrated an absolute failure to generate bone marrow B cells.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 NFATC1 Boaz Palterer gene: NFATC1 was added
gene: NFATC1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: NFATC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC1 were set to 37249233
Phenotypes for gene: NFATC1 were set to recurrent infections; hypogammaglobulinemia; decreased antibody responses
Penetrance for gene: NFATC1 were set to unknown
Review for gene: NFATC1 was set to RED
Added comment: NFATC1 encodes the nuclear factor of activated T cells 1, a key transcription factor critical for T and B cell activation, proliferation, and adaptive immune homeostasis.

Kostel Bal et al. identified 3 patients from 1 family carrying biallelic pathogenic NFATC1 missense variants presenting with recurrent infections, hypogammaglobulinemia, and decreased antibody responses due to these profound metabolic and proliferative defects.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 NFATC2 Boaz Palterer gene: NFATC2 was added
gene: NFATC2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: NFATC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFATC2 were set to 35789258
Phenotypes for gene: NFATC2 were set to progressive joint contractures; osteochondromas; B cell malignancy; diarrhea; chronic lung disease; hypogammaglobulinemia
Penetrance for gene: NFATC2 were set to unknown
Review for gene: NFATC2 was set to RED
Added comment: NFATC2 (also known as NFAT1) encodes the nuclear factor of activated T cells 2, a critical calcium/calcineurin-dependent transcription factor essential for T cell activation, immune homeostasis, and cell fate regulation.

Sharma et al. identified 1 patient from 1 family carrying a homozygous pathogenic NFATC2 frameshift variant (p.Tyr675Thrfs*18) presenting with progressive joint contractures, osteochondromas, and B cell malignancy.

Bustamante-Ogando et al. identified 1 patient from 1 family carrying compound heterozygous NFATC2 missense variants (p.Gly408Arg/p.Arg646Gln) presenting with severe early-onset immunodeficiency, recurrent sinopulmonary infections, bloody diarrhea, chronic lung disease, and pan-hypogammaglobulinemia.
( https://doi.org/10.70962/LASID2025abstract.69 )
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 KARS Boaz Palterer gene: KARS was added
gene: KARS was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: KARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KARS were set to 37770806
Phenotypes for gene: KARS were set to progressive leukoencephalopathy; peripheral neuropathy; deafness; antibody deficiency; hypogammaglobulinemia
Penetrance for gene: KARS were set to unknown
Review for gene: KARS was set to GREEN
Added comment: KARS1 encodes lysyl-tRNA synthetase, an enzyme crucial for protein translation in both the cytoplasm and mitochondria.

Classically associated with a multisystemic condition involving progressive leukoencephalopathy, peripheral neuropathy, and deafness, recent evidence establishes KARS1 defects as an Inborn Error of Immunity (IEI) characterized by B cell metabolic impairment and antibody deficiency.

Saettini et al. identified 1 patient from 1 family carrying pathogenic biallelic KARS1 variants (p.Phe291Val/p.Pro499Leu) presenting with hypogammaglobulinemia, recurrent infections, and impaired B cell activity.
From literature review 17 patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 IKBKE Boaz Palterer gene: IKBKE was added
gene: IKBKE was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: IKBKE was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IKBKE were set to 37937644
Phenotypes for gene: IKBKE were set to Herpes Simplex Virus type 2 (HSV-2) meningitis; Mollaret meningitis
Penetrance for gene: IKBKE were set to unknown
Review for gene: IKBKE was set to RED
Added comment: IKBKE encodes IKKε (Inhibitor of nuclear factor kappa-B kinase subunit epsilon), a noncanonical IκB kinase that plays a nonredundant role in mediating the innate immune response to viral infections.

Reyahi et al. identified a monoallelic truncating variant in IKBKE (c.312delC) as the cause of highly disabling, recurrent Herpes Simplex Virus type 2 (HSV-2) meningitis. Functional analyses demonstrate that this mutated allele encodes a truncated protein lacking kinase activity, which exerts a dominant-negative effect over the wild-type protein. This results in a functional deficiency within the cGAS/STING pathway, impaired STING phosphorylation, and a failure of patient cells (including stem cell-derived microglia) to mount an adequate IFN-β antiviral response against HSV-2 and double-stranded DNA.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 GINS4 Boaz Palterer gene: GINS4 was added
gene: GINS4 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: GINS4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS4 were set to 36345943
Phenotypes for gene: GINS4 were set to NK cell deficiency; neutropenia; viral infections
Penetrance for gene: GINS4 were set to unknown
Review for gene: GINS4 was set to RED
Added comment: Conte et al. described a familial NKD case in which 2 siblings had a substantive NKD and neutropenia in the absence of other immune system abnormalities. Exome sequencing identified compound heterozygous variants in Go-Ichi-Ni-San (GINS) complex subunit 4 (GINS4, also known as SLD5), an essential component of the human replicative helicase, which we demonstrate to have a damaging impact upon the expression and assembly of the GINS complex.

Cells derived from affected individuals and a GINS4-knockdown cell line demonstrate delayed cell cycle progression, without signs of improper DNA synthesis or increased replication stress.
Sources: Literature
Familial melanoma v2.10 CHEK2 Ida Ertmanska Classified gene: CHEK2 as Amber List (moderate evidence)
Familial melanoma v2.10 CHEK2 Ida Ertmanska Added comment: Comment on list classification: While there is emerging evidence for association of CHEK2 variants with risk of melanoma (e.g., PMID: 42177185), there are several studies that did not find a significant association. Hence, this gene can only be rated Amber with the current evidence.
Familial melanoma v2.10 CHEK2 Ida Ertmanska Gene: chek2 has been classified as Amber List (Moderate Evidence).
Familial melanoma v2.9 CHEK2 Ida Ertmanska Phenotypes for gene: CHEK2 were changed from Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265 to Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265; mucosal melanoma, MONDO:0000544; uveal melanoma, MONDO:0006486
Familial melanoma v2.8 CHEK2 Ida Ertmanska Phenotypes for gene: CHEK2 were changed from Mucosal melanoma to Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265
Familial melanoma v2.7 CHEK2 Ida Ertmanska Publications for gene: CHEK2 were set to PMID: 42177185
Familial melanoma v2.6 CHEK2 Ida Ertmanska Mode of inheritance for gene: CHEK2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial melanoma v2.5 CHEK2 Ida Ertmanska reviewed gene: CHEK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 32531112, 40283643; Phenotypes: Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 NOX1 Boaz Palterer gene: NOX1 was added
gene: NOX1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: NOX1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NOX1 were set to 32064493; 26301257; 29091079
Phenotypes for gene: NOX1 were set to Inflammatory bowel disease; IBD; VEOIBD
Penetrance for gene: NOX1 were set to unknown
Review for gene: NOX1 was set to RED
Added comment: NOX1 is an X-linked gene encoding NADPH Oxidase 1, an enzyme highly expressed in the colonic epithelium. At the apical brush border, NOX1 constitutively generates reactive oxygen species (ROS) into the crypt lumen. This localized ROS production is a critical component of the intestinal epithelial barrier, mediating innate antimicrobial defense and regulating host-microbe interactions at the mucosal interface without playing a role in systemic phagocytic oxidative bursts.

Defects in NOX1 are associated with mucosal immune dysregulation and Very Early-Onset Inflammatory Bowel Disease (VEO-IBD). Hemizygous loss-of-function missense variants (e.g., p.N122H) have been identified in male patients presenting with severe, early-onset ulcerative colitis-like pathology and pancolitis. Functional analyses of patient-derived organoids and ex vivo colonic explants demonstrate that these variants profoundly abrogate epithelial ROS production, leading to impaired host resistance to enteric microbes and subsequent severe intestinal inflammation (Hayes et al., 2015; Schwerd et al., 2018).

Unlike defects in the phagocytic NADPH oxidase (CYBB/NOX2), which cause classical Chronic Granulomatous Disease with systemic susceptibility to infection, NOX1 deficiency specifically impairs the epithelial innate immune compartment. Furthermore, large cohort analyses suggest that NOX1 loss-of-function variants may not always present as a fully penetrant Mendelian disorder, but rather act as a high-impact genetic modifier that drastically lowers the threshold for VEO-IBD when combined with specific microbial or environmental triggers (Schwerd et al., 2018).
Sources: Literature
Adult solid tumours cancer susceptibility v2.39 CHEK2 Ida Ertmanska changed review comment from: PMID: 40335619 Stubbins et al., 2025
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.

PMID: 39966186 Weis et al., 2025
Description of 12 patients - Brazilian women with early-stage breast cancer and CHEK2 variants (9/12 with onset before age 50yrs, and 9/12 had family history of breast cancer). 7 patients had intronic CHEK2 variants; the most common variant in this group was CHEK2: c.349A>G, p.Arg117Gly (4 patients).

PMID: 25798211 Kaczmarek-Rys et al., 2015
Polish cohort of 602 thyroid carcinoma patients and 829 controls. CHEK2 c.470 T > C (p.I157T, rs17879961) variant increases risk of thyroid carcinoma in Greater Poland population: increases the risk of developing differentiated thyroid cancer almost twice (OR = 1.81, p = 0.004), and the risk of papillary thyroid carcinoma in female patients homozygous for the c.470C allele was shown to increase almost 13-fold (OR = 12.81, p = 0.019).

CHEK2 is associated with Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265 (OMIM accessed 17th Jun 2026. The association between CHEK2 and AD CHEK2-related cancer predisposition was classified as Definitive in ClinGen (Hereditary Cancer GCEP, Nov 2024).; to: PMID: 40335619 Stubbins et al., 2025
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.

PMID: 39966186 Weis et al., 2025
Description of 12 patients - Brazilian women with early-stage breast cancer and CHEK2 variants (9/12 with onset before age 50yrs, and 9/12 had family history of breast cancer). 7 patients had intronic CHEK2 variants; the most common variant in this group was CHEK2: c.349A>G, p.Arg117Gly (4 patients).

PMID: 36360192 Kirchner et al., 2022
Study of a cohort of 150 Croatian men with prostate cancer, plus 442 cancer-free controls. 4/150 individuals harboured a P/LP variant in CHEK2, and developed prostate cancer on average almost 9 years earlier than individuals without CHEK2 variants.

PMID: 25798211 Kaczmarek-Rys et al., 2015
Polish cohort of 602 thyroid carcinoma patients and 829 controls. CHEK2 c.470 T > C (p.I157T, rs17879961) variant increases risk of thyroid carcinoma in Greater Poland population: increases the risk of developing differentiated thyroid cancer almost twice (OR = 1.81, p = 0.004), and the risk of papillary thyroid carcinoma in female patients homozygous for the c.470C allele was shown to increase almost 13-fold (OR = 12.81, p = 0.019).

CHEK2 is associated with Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265 (OMIM accessed 17th Jun 2026. The association between CHEK2 and AD CHEK2-related cancer predisposition was classified as Definitive in ClinGen (Hereditary Cancer GCEP, Nov 2024).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 DUOX2 Boaz Palterer gene: DUOX2 was added
gene: DUOX2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: DUOX2 was set to Unknown
Publications for gene: DUOX2 were set to 38075699; 26301257; 35429653
Phenotypes for gene: DUOX2 were set to Inflammatory bowel disease; IBD; VEOIBD
Penetrance for gene: DUOX2 were set to unknown
Review for gene: DUOX2 was set to GREEN
Added comment: 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
Adult solid tumours cancer susceptibility v2.39 CHEK2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous individuals reported with CHEK2 variants and solid tumors. Hence, this gene will be suggested for promotion to Green on Adult solid tumours cancer susceptibility, with a request of expert review to determine if the gene fits into panel scope.; to: Comment on list classification: There are numerous individuals reported with CHEK2 variants and solid tumors e.g., in breast, thyroid, and prostate cancer. Hence, this gene will be suggested for promotion to Green on Adult solid tumours cancer susceptibility, with a request of expert review to determine if the gene fits into panel scope.
Adult solid tumours cancer susceptibility v2.39 CHEK2 Ida Ertmanska changed review comment from: Comment on list classification: There are numerous individuals reported with CHEK2 variants (most often p.Ile157Thr) and solid tumors. Hence, this gene will be suggested for promotion to Green on Adult solid tumours cancer susceptibility, with a request of expert review to determine if the gene fits into panel scope.; to: Comment on list classification: There are numerous individuals reported with CHEK2 variants and solid tumors. Hence, this gene will be suggested for promotion to Green on Adult solid tumours cancer susceptibility, with a request of expert review to determine if the gene fits into panel scope.
Adult solid tumours cancer susceptibility v2.39 CHEK2 Ida Ertmanska changed review comment from: PMID: 40335619 Stubbins et al., 2025
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.

PMID: 39966186 Weis et al., 2025
Description of 12 patients - Brazilian women with early-stage breast cancer and CHEK2 variants (9/12 with onset before age 50yrs, and 9/12 had family history of breast cancer). 7 patients had intronic CHEK2 variants; the most common variant in this group was CHEK2: c.349A>G, p.Arg117Gly (4 patients).

PMID: 25798211 Kaczmarek-Rys et al., 2015
Polish cohort of 602 thyroid carcinoma patients and 829 controls. CHEK2 c.470 T > C (p.I157T, rs17879961) variant increases risk of thyroid carcinoma in Greater Poland population: increases the risk of developing differentiated thyroid cancer almost twice (OR = 1.81, p = 0.004), and the risk of papillary thyroid carcinoma in female patients homozygous for the c.470C allele was shown to increase almost 13-fold (OR = 12.81, p = 0.019).

CHEK2 is associated with Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265 (OMIM accessed 17th Jun 2026.; to: PMID: 40335619 Stubbins et al., 2025
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.

PMID: 39966186 Weis et al., 2025
Description of 12 patients - Brazilian women with early-stage breast cancer and CHEK2 variants (9/12 with onset before age 50yrs, and 9/12 had family history of breast cancer). 7 patients had intronic CHEK2 variants; the most common variant in this group was CHEK2: c.349A>G, p.Arg117Gly (4 patients).

PMID: 25798211 Kaczmarek-Rys et al., 2015
Polish cohort of 602 thyroid carcinoma patients and 829 controls. CHEK2 c.470 T > C (p.I157T, rs17879961) variant increases risk of thyroid carcinoma in Greater Poland population: increases the risk of developing differentiated thyroid cancer almost twice (OR = 1.81, p = 0.004), and the risk of papillary thyroid carcinoma in female patients homozygous for the c.470C allele was shown to increase almost 13-fold (OR = 12.81, p = 0.019).

CHEK2 is associated with Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265 (OMIM accessed 17th Jun 2026. The association between CHEK2 and AD CHEK2-related cancer predisposition was classified as Definitive in ClinGen (Hereditary Cancer GCEP, Nov 2024).
Adult solid tumours cancer susceptibility v2.39 CHEK2 Ida Ertmanska edited their review of gene: CHEK2: Changed publications to: 25798211, 39966186, 40335619
Adult solid tumours cancer susceptibility v2.39 CHEK2 Ida Ertmanska changed review comment from: PMID: 40335619 Stubbins et al., 2025
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.; to: PMID: 40335619 Stubbins et al., 2025
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.

PMID: 39966186 Weis et al., 2025
Description of 12 patients - Brazilian women with early-stage breast cancer and CHEK2 variants (9/12 with onset before age 50yrs, and 9/12 had family history of breast cancer). 7 patients had intronic CHEK2 variants; the most common variant in this group was CHEK2: c.349A>G, p.Arg117Gly (4 patients).

PMID: 25798211 Kaczmarek-Rys et al., 2015
Polish cohort of 602 thyroid carcinoma patients and 829 controls. CHEK2 c.470 T > C (p.I157T, rs17879961) variant increases risk of thyroid carcinoma in Greater Poland population: increases the risk of developing differentiated thyroid cancer almost twice (OR = 1.81, p = 0.004), and the risk of papillary thyroid carcinoma in female patients homozygous for the c.470C allele was shown to increase almost 13-fold (OR = 12.81, p = 0.019).

CHEK2 is associated with Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265 (OMIM accessed 17th Jun 2026.
Adult solid tumours cancer susceptibility v2.39 CHEK2 Ida Ertmanska Phenotypes for gene: CHEK2 were changed from Breast cancer to Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265
Adult solid tumours cancer susceptibility v2.38 CHEK2 Ida Ertmanska Publications for gene: CHEK2 were set to
Adult solid tumours cancer susceptibility v2.37 CHEK2 Ida Ertmanska Classified gene: CHEK2 as Amber List (moderate evidence)
Adult solid tumours cancer susceptibility v2.37 CHEK2 Ida Ertmanska Added comment: Comment on list classification: There are numerous individuals reported with CHEK2 variants (most often p.Ile157Thr) and solid tumors. Hence, this gene will be suggested for promotion to Green on Adult solid tumours cancer susceptibility, with a request of expert review to determine if the gene fits into panel scope.
Adult solid tumours cancer susceptibility v2.37 CHEK2 Ida Ertmanska Gene: chek2 has been classified as Amber List (Moderate Evidence).
Adult solid tumours cancer susceptibility v2.36 CHEK2 Ida Ertmanska Mode of inheritance for gene: CHEK2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult solid tumours cancer susceptibility v2.35 CHEK2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CHEK2.
Tag Q2_26_expert_review tag was added to gene: CHEK2.
Adult solid tumours cancer susceptibility v2.35 CHEK2 Ida Ertmanska reviewed gene: CHEK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40335619; Phenotypes: Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 PTPN6 Boaz Palterer changed review comment from: Conference presentation CIS 2026 (https://clinimmsoc.org/BaseV69/CIS2026abstracts-FINAL.pdf)
Farsh Moussavi-Harami described in six children from four unrelated kindreds presenting with severe infant-onset hemolytic anemia, life-threatening inflammatory, lung disease, and severe pulmonary infections. Exome sequencing revealed biallelic coding variants in PTPN6. All SHP1 variants areabsent from gnomAD and are predicted to be damaging by multiple prediction algorithms. The variants are all clustered within the SHP1 phosphatase domain, which mediates the removal of phosphate groups from signaling proteins. Functional studies demonstrate that these variants destabilize SHP1 protein levels and markedly reduce or abolish the SHP1 phosphatase activity. These mutant SHP1 proteins also fail to appropriately downregulate ERK signaling following cell stimulation. Bulk RNA sequencing (RNA-seq) from one affected patient showedprofoundly heightened inflammatory gene signatures, placing this individual as an outlier relative to a pediatric septic shock cohort,particularly within IL-6/STAT3, TNFα/NFkB, and general inflammatory pathways. These findings parallel phenotypes observed in SHP1-deficient mouse models, which also develop hyperinflammatory disease and anemia due to loss of SHP1-mediated negative regulation.Collectively, these clinical and experimental data establish PTPN6 loss-of-function as the cause of a severe, newly recognized PIRD characterized by infant-onset severe anemia and life-threatening inflammatory pulmonary disease.
Sources: Other; to: Conference presentation CIS 2026 (https://doi.org/10.70962/cis2026abstract.18)
Farsh Moussavi-Harami described in six children from four unrelated kindreds presenting with severe infant-onset hemolytic anemia, life-threatening inflammatory, lung disease, and severe pulmonary infections. Exome sequencing revealed biallelic coding variants in PTPN6. All SHP1 variants areabsent from gnomAD and are predicted to be damaging by multiple prediction algorithms. The variants are all clustered within the SHP1 phosphatase domain, which mediates the removal of phosphate groups from signaling proteins. Functional studies demonstrate that these variants destabilize SHP1 protein levels and markedly reduce or abolish the SHP1 phosphatase activity. These mutant SHP1 proteins also fail to appropriately downregulate ERK signaling following cell stimulation. Bulk RNA sequencing (RNA-seq) from one affected patient showedprofoundly heightened inflammatory gene signatures, placing this individual as an outlier relative to a pediatric septic shock cohort,particularly within IL-6/STAT3, TNFα/NFkB, and general inflammatory pathways. These findings parallel phenotypes observed in SHP1-deficient mouse models, which also develop hyperinflammatory disease and anemia due to loss of SHP1-mediated negative regulation.Collectively, these clinical and experimental data establish PTPN6 loss-of-function as the cause of a severe, newly recognized PIRD characterized by infant-onset severe anemia and life-threatening inflammatory pulmonary disease.
Sources: Other
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 PTPN6 Boaz Palterer gene: PTPN6 was added
gene: PTPN6 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Other
Mode of inheritance for gene: PTPN6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PTPN6 were set to Autoimmune cytopenias; hemolytic anemia; interstitial lung disease
Penetrance for gene: PTPN6 were set to unknown
Review for gene: PTPN6 was set to GREEN
Added comment: Conference presentation CIS 2026 (https://clinimmsoc.org/BaseV69/CIS2026abstracts-FINAL.pdf)
Farsh Moussavi-Harami described in six children from four unrelated kindreds presenting with severe infant-onset hemolytic anemia, life-threatening inflammatory, lung disease, and severe pulmonary infections. Exome sequencing revealed biallelic coding variants in PTPN6. All SHP1 variants areabsent from gnomAD and are predicted to be damaging by multiple prediction algorithms. The variants are all clustered within the SHP1 phosphatase domain, which mediates the removal of phosphate groups from signaling proteins. Functional studies demonstrate that these variants destabilize SHP1 protein levels and markedly reduce or abolish the SHP1 phosphatase activity. These mutant SHP1 proteins also fail to appropriately downregulate ERK signaling following cell stimulation. Bulk RNA sequencing (RNA-seq) from one affected patient showedprofoundly heightened inflammatory gene signatures, placing this individual as an outlier relative to a pediatric septic shock cohort,particularly within IL-6/STAT3, TNFα/NFkB, and general inflammatory pathways. These findings parallel phenotypes observed in SHP1-deficient mouse models, which also develop hyperinflammatory disease and anemia due to loss of SHP1-mediated negative regulation.Collectively, these clinical and experimental data establish PTPN6 loss-of-function as the cause of a severe, newly recognized PIRD characterized by infant-onset severe anemia and life-threatening inflammatory pulmonary disease.
Sources: Other
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 OSMR Boaz Palterer gene: OSMR was added
gene: OSMR was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: OSMR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSMR were set to 42221229
Phenotypes for gene: OSMR were set to Atopic dermatitis; eosinophilia; elevated IgE
Penetrance for gene: OSMR were set to unknown
Review for gene: OSMR was set to GREEN
Added comment: Samra et al. identified 10 affected individuals from seven unrelated families with germline biallelic loss-of-function variants in OSMR who shared a phenotype of early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. All patient-derived OSMRβ variants failed to localize to the cell surface, resulting in selective loss of OSM-dependent signaling. Patient cells showed markedly reduced OSM-induced phosphorylation of STAT1, STAT3, and STAT5, while signaling through other IL-6 family receptor complexes remained intact. Transcriptomic profiling of patient primary dermal fibroblasts revealed consistent downstream effects, including loss of interferon-responsive and inflammatory gene programs. Re-expression of wild-type OSMR restored receptor surface expression, STAT activation, and transcriptional responses, confirming a causal loss-of-function mechanism. Together, these findings establish biallelic OSMR deficiency as a novel primary atopic disorder.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v5.6 ACKR1 Ida Ertmanska changed review comment from: PMID: 35994632 Merz et al., 2023
The study found that 66.7% (80 of 120) of Black individuals had the Duffy-null phenotype and that there is a significant difference in absolute neutrophil counts (ANCs) between Duffy-null and Duffy non-null individuals (P < 0.001). Additionally, 19 of 80 (23.8%) Duffy-null individuals had an ANC of <2000 cells per μL compared with no Duffy non-null individuals. The Duffy-null phenotype is clinically insignificant; however, authors postulate Duffy-null-specific ANC reference ranges should be developed, and the term 'benign ethnic neutropenia' should be replaced with 'Duffy-null associated neutrophil count'.

https://www.hematology.org/education/danc - Duffy-null individuals have no increased risk of infection but are often incorrectly labeled as having neutropenia - reason for inclusion of this gene
Duffy null is characterized by the presence of Fy(b) antibodies on nonerythroid cells, but an absence of Fy(b) on erythrocytes.

ACKR1 is associated with AD, AR [Blood group, Duffy system], OMIM:110700 in OMIM (accessed 17th Jun 2026).; to: PMID: 35994632 Merz et al., 2023
The study found that 66.7% (80 of 120) of Black individuals had the Duffy-null phenotype and that there is a significant difference in absolute neutrophil counts (ANCs) between Duffy-null and Duffy non-null individuals (P < 0.001). Additionally, 19 of 80 (23.8%) Duffy-null individuals had an ANC of <2000 cells per μL compared with no Duffy non-null individuals. The Duffy-null phenotype is clinically insignificant; however, authors postulate Duffy-null-specific ANC reference ranges should be developed, and the term 'benign ethnic neutropenia' should be replaced with 'Duffy-null associated neutrophil count'.

https://www.hematology.org/education/danc - Duffy-null individuals have no increased risk of infection but are often incorrectly labeled as having neutropenia - reason for inclusion of this gene

ACKR1 is associated with AD, AR [Blood group, Duffy system], OMIM:110700 in OMIM (accessed 17th Jun 2026).
Duffy null is characterized by the presence of Fy(b) antibodies on nonerythroid cells, but an absence of Fy(b) on erythrocytes.
Cytopenia - NOT Fanconi anaemia v5.6 ACKR1 Ida Ertmanska changed review comment from: PMID: 35994632 Merz et al., 2023
The study found that 66.7% (80 of 120) of Black individuals had the Duffy-null phenotype and that there is a significant difference in absolute neutrophil counts (ANCs) between Duffy-null and Duffy non-null individuals (P < 0.001). Additionally, 19 of 80 (23.8%) Duffy-null individuals had an ANC of <2000 cells per μL compared with no Duffy non-null individuals. The Duffy-null phenotype is clinically insignificant; however, authors postulate Duffy-null-specific ANC reference ranges should be developed, and the term 'benign ethnic neutropenia' should be replaced with 'Duffy-null associated neutrophil count'.

https://www.hematology.org/education/danc - Duffy-null individuals have no increased risk of infection but are often incorrectly labeled as having neutropenia - reason for inclusion of this gene

ACKR1 is associated with AD, AR [Blood group, Duffy system], OMIM:110700 in OMIM (accessed 17th Jun 2026).; to: PMID: 35994632 Merz et al., 2023
The study found that 66.7% (80 of 120) of Black individuals had the Duffy-null phenotype and that there is a significant difference in absolute neutrophil counts (ANCs) between Duffy-null and Duffy non-null individuals (P < 0.001). Additionally, 19 of 80 (23.8%) Duffy-null individuals had an ANC of <2000 cells per μL compared with no Duffy non-null individuals. The Duffy-null phenotype is clinically insignificant; however, authors postulate Duffy-null-specific ANC reference ranges should be developed, and the term 'benign ethnic neutropenia' should be replaced with 'Duffy-null associated neutrophil count'.

https://www.hematology.org/education/danc - Duffy-null individuals have no increased risk of infection but are often incorrectly labeled as having neutropenia - reason for inclusion of this gene
Duffy null is characterized by the presence of Fy(b) antibodies on nonerythroid cells, but an absence of Fy(b) on erythrocytes.

ACKR1 is associated with AD, AR [Blood group, Duffy system], OMIM:110700 in OMIM (accessed 17th Jun 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 MYB Boaz Palterer gene: MYB was added
gene: MYB was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: MYB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MYB were set to Evans syndrome; Neutropenia; Autoimmune cytopenias; B cell lymphopenia
Penetrance for gene: MYB were set to Incomplete
Review for gene: MYB was set to GREEN
Added comment: Aaron Boothby et al. presented ten heterozygous germline MYB variants in seven families and four unrelated singletons. The variants segregated with autoimmune cytopenias, including Evans syndrome, in three five-generation pedigrees. In our cohort of 41 carriers, 22 were affected by autoimmune cytopenias, while one had isolated B cell lymphopenia and neutropenia.

https://rupress.org/jhi/article/2/CIS2026/eCIS2026abstract.16/281957/MYB-Haploinsufficiency-Causes-Familial-Autoimmune
Sources: Literature
Cytopenia - NOT Fanconi anaemia v5.6 ACKR1 Ida Ertmanska Classified gene: ACKR1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v5.6 ACKR1 Ida Ertmanska Added comment: Comment on list classification: The ACKR1-related Duffy-null phenotype (or ACKR1/DARC-associated neutropenia, ADAN) is fairly common, particularly in Black individuals. However, as reviewed by Carl Fratter, diagnosis of ADAN would explain the mildly reduced neutrophil counts and help guide further clinical management of patients.
Cytopenia - NOT Fanconi anaemia v5.6 ACKR1 Ida Ertmanska Gene: ackr1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v5.5 ACKR1 Ida Ertmanska Phenotypes for gene: ACKR1 were changed from 613665 Benign hereditary neutropenia to [Blood group, Duffy system], OMIM:110700; Duffy blood group, HP:0032373
Structural eye disease v5.6 TBK1 Nicky Cronbach gene: TBK1 was added
gene: TBK1 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: TBK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBK1 were set to PMID: 21447600; 31563868; 33892047; 2774031
Phenotypes for gene: TBK1 were set to Juvenile open angle glaucoma; Juvenile normal tension glaucoma; HP:0001087 developmental glaucoma; HP:0012108 open angle glaucoma; HP:0000501 glaucoma
Penetrance for gene: TBK1 were set to unknown
Review for gene: TBK1 was set to GREEN
Added comment: Autosomal dominant juvenile and adult-onset normal tension and open angle glaucoma. More than 3 families reported. PMID 2774031 reports a family with juvenile normal tension glaucoma from 13 years of age, who have subsequently been reported to have a TBK1 dominant variant (PMID 34536459).
Sources: Literature
Cytopenia - NOT Fanconi anaemia v5.4 ACKR1 Ida Ertmanska Publications for gene: ACKR1 were set to
Cytopenia - NOT Fanconi anaemia v5.3 ACKR1 Ida Ertmanska Mode of inheritance for gene: ACKR1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v5.2 ACKR1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: ACKR1.
Tag Q2_26_NHS_review tag was added to gene: ACKR1.
Cytopenia - NOT Fanconi anaemia v5.2 ACKR1 Ida Ertmanska changed review comment from: PMID: 35994632 Merz et al., 2023
The study found that 66.7% (80 of 120) of Black individuals had the Duffy-null phenotype and that there is a significant difference in absolute neutrophil counts (ANCs) between Duffy-null and Duffy non-null individuals (P < 0.001). Additionally, 19 of 80 (23.8%) Duffy-null individuals had an ANC of <2000 cells per μL compared with no Duffy non-null individuals. The Duffy-null phenotype is clinically insignificant; however, authors postulate Duffy-null-specific ANC reference ranges should be developed, and the term 'benign ethnic neutropenia' should be replaced with 'Duffy-null associated neutrophil count'.

ACKR1 is associated with AD, AR [Blood group, Duffy system], OMIM:110700 in OMIM (accessed 17th Jun 2026).; to: PMID: 35994632 Merz et al., 2023
The study found that 66.7% (80 of 120) of Black individuals had the Duffy-null phenotype and that there is a significant difference in absolute neutrophil counts (ANCs) between Duffy-null and Duffy non-null individuals (P < 0.001). Additionally, 19 of 80 (23.8%) Duffy-null individuals had an ANC of <2000 cells per μL compared with no Duffy non-null individuals. The Duffy-null phenotype is clinically insignificant; however, authors postulate Duffy-null-specific ANC reference ranges should be developed, and the term 'benign ethnic neutropenia' should be replaced with 'Duffy-null associated neutrophil count'.

https://www.hematology.org/education/danc - Duffy-null individuals have no increased risk of infection but are often incorrectly labeled as having neutropenia - reason for inclusion of this gene

ACKR1 is associated with AD, AR [Blood group, Duffy system], OMIM:110700 in OMIM (accessed 17th Jun 2026).
Cytopenia - NOT Fanconi anaemia v5.2 ACKR1 Ida Ertmanska edited their review of gene: ACKR1: Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v5.2 ACKR1 Ida Ertmanska reviewed gene: ACKR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35994632; Phenotypes: [Blood group, Duffy system], OMIM:110700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.22 TRAPPC2L Ida Ertmanska Phenotypes for gene: TRAPPC2L were changed from encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, MONDO:0032681; Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331 to encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, MONDO:0032681; Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331
Intellectual disability v10.22 TRAPPC2L Ida Ertmanska Phenotypes for gene: TRAPPC2L were changed from Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331 to encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, MONDO:0032681; Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331
Intellectual disability v10.21 TRAPPC2L Ida Ertmanska Publications for gene: TRAPPC2L were set to 30120216; 32843486
Intellectual disability v10.20 TRAPPC2L Ida Ertmanska Classified gene: TRAPPC2L as Amber List (moderate evidence)
Intellectual disability v10.20 TRAPPC2L Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated families with biallelic TRAPPC2L variants (3 with missense and 1 with nonsense variants), with syndromic neurodevelopmental delay. Hence, this gene can be promoted to Green on Intellectual disability at the next update.
Intellectual disability v10.20 TRAPPC2L Ida Ertmanska Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.19 TRAPPC2L Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TRAPPC2L.
Intellectual disability v10.19 TRAPPC2L Ida Ertmanska reviewed gene: TRAPPC2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 36849228; Phenotypes: encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, MONDO:0032681, Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v6.3 TRAPPC2L Ida Ertmanska Classified gene: TRAPPC2L as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v6.3 TRAPPC2L Ida Ertmanska Added comment: Comment on list classification: While there are 4 unrelated families reported with biallelic TRAPPC2L variants, the main clinical presentation was global developmental delay. Episodic rhabdomyolysis was noted in 2 patients (homozygous for the same variant), and congenital hypotonia with elevated CK was seen in a third family. However, more evidence is required to confirm that these patients have TRAPPC2L-related rhabdomyolysis. Hence, this gene should remain Amber with the current evidence.
Rhabdomyolysis and metabolic muscle disorders v6.3 TRAPPC2L Ida Ertmanska Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v6.2 TRAPPC2L Ida Ertmanska gene: TRAPPC2L was added
gene: TRAPPC2L was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486; 36849228
Phenotypes for gene: TRAPPC2L were set to encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, MONDO:0032681; Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: PMID: 30120216 Milev et al., 2018
Two unrelated probands with homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

PMID: 32843486 Al-Deri et al., 2020
Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.
The siblings have not had their serum creatine kinase levels measured, and there been no manifestations of a myopathy.

PMID: 36849228 Abaji et al., 2023
2 sibs (boy and girl) with a neurodevelopmental disorder - both had severe developmental delay (absent speech, walking absent in IV-3, sister IV-4 started walking at 7-9 years old), hypotonia, mild dysmorphic features, non-specific MRI changes (e.g., thin corpus callosum, delayed myelination), stereotyped hand movements. No regression of skills was noted. WES revealed a homozygous c.367C>T, p.Gln123Ter variant in TRAPPC2L. Unaffected family members confirmed WT / het. Both patients had elevated CK, but muscle biopsy in patient IV-4 showed normal morphology and no histoenzymatic alterations. Authors argue it may be too early in life to see musculary dystrophy features on biopsy.

TRAPPC2L is associated with AR Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, MIM:618331 (OMIM accessed 17th Jun 2026).
Sources: Literature
Congenital muscular dystrophy v7.18 TRAPPC2L Ida Ertmanska changed review comment from: Comment on list classification: While there are 4 unrelated families reported with biallelic TRAPPC2L variants, the main clinical presentation was global developmental delay. Episodic rhabdomyolysis was noted in 2 patients (homozygous for the same variant), and congenital hypotonia with elevated CK was seen in a third family. However, more evidence is required to confirm that these patients have TRAPPC2L-related congenital myopathy. Hence, this gene should remain Amber with the current evidence.; to: Comment on list classification: While there are 4 unrelated families reported with biallelic TRAPPC2L variants, the main clinical presentation was global developmental delay. Episodic rhabdomyolysis was noted in 2 patients (homozygous for the same variant), and congenital hypotonia with elevated CK was seen in a third family. However, more evidence is required to confirm that these patients have TRAPPC2L-related muscular dystrophy. Hence, this gene should remain Amber with the current evidence.
Congenital muscular dystrophy v7.18 TRAPPC2L Ida Ertmanska Phenotypes for gene: TRAPPC2L were changed from to encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, MONDO:0032681; Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331
Congenital muscular dystrophy v7.17 TRAPPC2L Ida Ertmanska Publications for gene: TRAPPC2L were set to
Congenital muscular dystrophy v7.16 TRAPPC2L Ida Ertmanska Classified gene: TRAPPC2L as Amber List (moderate evidence)
Congenital muscular dystrophy v7.16 TRAPPC2L Ida Ertmanska Added comment: Comment on list classification: While there are 4 unrelated families reported with biallelic TRAPPC2L variants, the main clinical presentation was global developmental delay. Episodic rhabdomyolysis was noted in 2 patients (homozygous for the same variant), and congenital hypotonia with elevated CK was seen in a third family. However, more evidence is required to confirm that these patients have TRAPPC2L-related congenital myopathy. Hence, this gene should remain Amber with the current evidence.
Congenital muscular dystrophy v7.16 TRAPPC2L Ida Ertmanska Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v7.15 TRAPPC2L Ida Ertmanska reviewed gene: TRAPPC2L: Rating: AMBER; Mode of pathogenicity: None; Publications: 30120216, 32843486, 36849228; Phenotypes: Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, OMIM:618331; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v5.6 OPTN Nicky Cronbach reviewed gene: OPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37530275, 15326130, 29540704, 16043855, 33892047; Phenotypes: Juvenile open angle glaucoma, Juvenile normal tension glaucoma, HP:0001087 developmental glaucoma, HP:0012108 open angle glaucoma, HP:0000501 glaucoma; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital muscular dystrophy v7.15 HMGCR Arina Puzriakova Classified gene: HMGCR as Amber List (moderate evidence)
Congenital muscular dystrophy v7.15 HMGCR Arina Puzriakova Added comment: Comment on list classification: At least 6 unrelated families have been reported with HMGCR-related limb-girdle muscular dystrophy. Age of onset is variable but has been reported as early as 4 months and therefore this gene can be promoted to Green at the next GMS panel update.
Congenital muscular dystrophy v7.15 HMGCR Arina Puzriakova Gene: hmgcr has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v7.14 HMGCR Arina Puzriakova Phenotypes for gene: HMGCR were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 28, OMIM:620375
Congenital muscular dystrophy v7.13 HMGCR Arina Puzriakova Publications for gene: HMGCR were set to
Congenital muscular dystrophy v7.12 HMGCR Arina Puzriakova Tag Q2_26_promote_green tag was added to gene: HMGCR.
Tag Q2_26_NHS_review tag was added to gene: HMGCR.
Congenital muscular dystrophy v7.12 HMGCR Arina Puzriakova reviewed gene: HMGCR: Rating: GREEN; Mode of pathogenicity: None; Publications: 37167966, 36745799; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 28, OMIM:620375; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.8 TRIM32 Ida Ertmanska Phenotypes for gene: TRIM32 were changed from Limb-Girdle Muscular Dystrophy, Recessive; Muscular dystrophy, limb-girdle, type 2H, 254110; Limb-girdle muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 8, OMIM:254110; autosomal recessive limb-girdle muscular dystrophy type 2H, MONDO:0009683
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.7 TRIM32 Ida Ertmanska Publications for gene: TRIM32 were set to http://www.ncbi.nlm.nih.gov/books/NBK1408/
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.6 TRIM32 Ida Ertmanska reviewed gene: TRIM32: Rating: GREEN; Mode of pathogenicity: None; Publications: 17994549, 30823891, 37217920, 40017290; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 8, OMIM:254110, autosomal recessive limb-girdle muscular dystrophy type 2H, MONDO:0009683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.63 TRIM32 Ida Ertmanska changed review comment from: PMID: 17994549 Saccone et al., 2008
Proband 1 - 44yo Croatian woman with slowly progressive proximal muscle weakness and respiratory weakness (onset around 37 yrs), homozygous for TRIM32: c.1560del (p.Cys521fs) - rare in gnomAD v4.1.1, 4 hets reported
Proband 3 - man from Southern Italy with weakness and paresthesia (onset in 30s); muscle biopsy at age 59 yrs showed muscular dystrophy, diagnosed with LGMD; lost the ability to walk at age 64 yrs, with scapular winging and marked atrophy in the limbs; homozygous for TRIM32 c.1181G>A, p.Arg394His - rare in gnomAD, 36 hets reported
Proband 4 - 15yo boy with elevated CK and muscle cramps after exercise, but no muscle weakness; heterozygous for TRIM32: c.1762_1764del, p.Asp588del - 2 hets in gnomAD v4.1.1.

PMID: 30823891 Servián-Morilla et al., 2019
Report of three independent families of Spanish and Australian origin with a muscular dystrophy, with biallelic TRIM32 mutations:
Family A: affected members homozygous for TRIM32 c.1771G > A (p.V591 M) - onset in teenage years with foot drop, with no other symptoms until 3rd decade
Family B: affected members were comp het for TRIM32 c.650 A > G (p.N217S) and c.1701_1703del (p.F568del) - onset of weakness in 20s
Family C: homozygous TRIM32 c.115_116insT (p.C39LfsX17) mutation seen in affected members - onset of muscle weakness in 3rd / 4th decade of life
Segregation studies showed that available healthy family members were WT or heterozygous for TRIM32 variants.

PMID: 37217920 Guan et al., 2023
Proband II1 - Chinese woman, 30yo, presented with fatigue and muscle weakness during pregnancy - diagnosed with LGMD; onset around 24yrs; muscle biopsy showed myopathic features; compound het for TRIM32 variant c.1700A > G, p.H567R & 43 kb deletion (results in removal of whole TRIM32 as well as a portion of ASTN2 gene - not linked to disease in OMIM; Method: WGS + Sanger; parents healthy het

PMID: 40017290 Caputo & Schoser, 2024 - case follow up for PMID: 15786463
Case 1 - boy with muscle weakness and pain after exercise, first noted at 6yrs; the weakness was progressive, and he was wheelchair bound at age 38yrs, respiratory insufficiency was present at age 44yrs; homozygous for TRIM32 p.D487N variant
Case 2 - younger brother of Case 1, first presented at 32 years with exercise induced muscle pain; progressive muscle weakness led to wheelchair use, respiratory symptoms noted at age 52yrs; elevated CK; homozygous for TRIM32 p.D487N variant; to: PMID: 17994549 Saccone et al., 2008
Proband 1 - 44yo Croatian woman with slowly progressive proximal muscle weakness and respiratory weakness (onset around 37 yrs), homozygous for TRIM32: c.1560del (p.Cys521fs) - rare in gnomAD v4.1.1, 4 hets reported
Proband 3 - man from Southern Italy with weakness and paresthesia (onset in 30s); muscle biopsy at age 59 yrs showed muscular dystrophy, diagnosed with LGMD; lost the ability to walk at age 64 yrs, with scapular winging and marked atrophy in the limbs; homozygous for TRIM32 c.1181G>A, p.Arg394His - rare in gnomAD, 36 hets reported
Proband 4 - 15yo boy with elevated CK and muscle cramps after exercise, but no muscle weakness; heterozygous for TRIM32: c.1762_1764del, p.Asp588del - 2 hets in gnomAD v4.1.1.

PMID: 30823891 Servián-Morilla et al., 2019
Report of three independent families of Spanish and Australian origin with a muscular dystrophy, with biallelic TRIM32 mutations:
Family A: affected members homozygous for TRIM32 c.1771G > A (p.V591 M) - onset in teenage years with foot drop, with no other symptoms until 3rd decade
Family B: affected members were comp het for TRIM32 c.650 A > G (p.N217S) and c.1701_1703del (p.F568del) - onset of weakness in 20s
Family C: homozygous TRIM32 c.115_116insT (p.C39LfsX17) mutation seen in affected members - onset of muscle weakness in 3rd / 4th decade of life
Segregation studies showed that available healthy family members were WT or heterozygous for TRIM32 variants.

PMID: 37217920 Guan et al., 2023
Proband II1 - Chinese woman, 30yo, presented with fatigue and muscle weakness during pregnancy - diagnosed with LGMD; onset around 24yrs; muscle biopsy showed myopathic features; compound het for TRIM32 variant c.1700A > G, p.H567R & 43 kb deletion (results in removal of whole TRIM32 as well as a portion of ASTN2 gene - not linked to disease in OMIM; Method: WGS + Sanger; parents healthy het

PMID: 40017290 Caputo & Schoser, 2024 - case follow up for PMID: 15786463
Case 1 - boy with muscle weakness and pain after exercise, first noted at 6yrs; the weakness was progressive, and he was wheelchair bound at age 38yrs, respiratory insufficiency was present at age 44yrs; homozygous for TRIM32 p.D487N variant
Case 2 - younger brother of Case 1, first presented at 32 years with exercise induced muscle pain; progressive muscle weakness led to wheelchair use, respiratory symptoms noted at age 52yrs; elevated CK; homozygous for TRIM32 p.D487N variant

TRIM32 is associated with Muscular dystrophy, limb-girdle, autosomal recessive 8, OMIM:254110 (also Definitive in ClinGen, 2024), and AR ?Bardet-Biedl syndrome 11, OMIM:615988 (Limited in ClinGen, 2024) - resources accessed 17th June 2026.
Congenital myopathy v7.63 TRIM32 Ida Ertmanska edited their review of gene: TRIM32: Changed publications to: 17994549, 30823891, 37217920, 40017290
Congenital myopathy v7.63 TRIM32 Ida Ertmanska Phenotypes for gene: TRIM32 were changed from to Muscular dystrophy, limb-girdle, autosomal recessive 8, OMIM:254110; autosomal recessive limb-girdle muscular dystrophy type 2H, MONDO:0009683
Congenital myopathy v7.62 TRIM32 Ida Ertmanska Classified gene: TRIM32 as Red List (low evidence)
Congenital myopathy v7.62 TRIM32 Ida Ertmanska Added comment: Comment on list classification: There are numerous patients reported with biallelic TRIM32 variants and LGMD / myopathy features. However, the age of onset is usually in 20s-30s, with few cases of childhood onset. This is not in scope of the congenital myopathy panel. TRIM32 is already Green on the LGMD panel. Hence, it should remain Red on Congenital myopathy.
Congenital myopathy v7.62 TRIM32 Ida Ertmanska Gene: trim32 has been classified as Red List (Low Evidence).
Congenital myopathy v7.61 TRIM32 Ida Ertmanska changed review comment from: PMID: 17994549 Saccone et al., 2008
Proband 1 - 44yo Croatian woman with slowly progressive proximal muscle weakness and respiratory weakness (onset around 37 yrs), homozygous for TRIM32: c.1560del (p.Cys521fs) - rare in gnomAD v4.1.1, 4 hets reported
Proband 3 - man from Southern Italy with weakness and paresthesia (onset in 30s); muscle biopsy at age 59 yrs showed muscular dystrophy, diagnosed with LGMD; lost the ability to walk at age 64 yrs, with scapular winging and marked atrophy in the limbs; homozygous for TRIM32 c.1181G>A, p.Arg394His - rare in gnomAD, 36 hets reported
Proband 4 - 15yo boy with elevated CK and muscle cramps after exercise, but no muscle weakness; heterozygous for TRIM32: c.1762_1764del, p.Asp588del - 2 hets in gnomAD v4.1.1.

PMID: 37217920 Guan et al., 2023
Proband II1 - Chinese woman, 30yo, presented with fatigue and muscle weakness during pregnancy - diagnosed with LGMD; onset around 24yrs; muscle biopsy showed myopathic features; compound het for TRIM32 variant c.1700A > G, p.H567R & 43 kb deletion (results in removal of whole TRIM32 as well as a portion of ASTN2 gene - not linked to disease in OMIM; Method: WGS + Sanger; parents healthy het

PMID: 40017290 Caputo & Schoser, 2024 - case follow up for PMID: 15786463
Case 1 - boy with muscle weakness and pain after exercise, first noted at 6yrs; the weakness was progressive, and he was wheelchair bound at age 38yrs, respiratory insufficiency was present at age 44yrs; homozygous for TRIM32 p.D487N variant
Case 2 - younger brother of Case 1, first presented at 32 years with exercise induced muscle pain; progressive muscle weakness led to wheelchair use, respiratory symptoms noted at age 52yrs; elevated CK; homozygous for TRIM32 p.D487N variant; to: PMID: 17994549 Saccone et al., 2008
Proband 1 - 44yo Croatian woman with slowly progressive proximal muscle weakness and respiratory weakness (onset around 37 yrs), homozygous for TRIM32: c.1560del (p.Cys521fs) - rare in gnomAD v4.1.1, 4 hets reported
Proband 3 - man from Southern Italy with weakness and paresthesia (onset in 30s); muscle biopsy at age 59 yrs showed muscular dystrophy, diagnosed with LGMD; lost the ability to walk at age 64 yrs, with scapular winging and marked atrophy in the limbs; homozygous for TRIM32 c.1181G>A, p.Arg394His - rare in gnomAD, 36 hets reported
Proband 4 - 15yo boy with elevated CK and muscle cramps after exercise, but no muscle weakness; heterozygous for TRIM32: c.1762_1764del, p.Asp588del - 2 hets in gnomAD v4.1.1.

PMID: 30823891 Servián-Morilla et al., 2019
Report of three independent families of Spanish and Australian origin with a muscular dystrophy, with biallelic TRIM32 mutations:
Family A: affected members homozygous for TRIM32 c.1771G > A (p.V591 M) - onset in teenage years with foot drop, with no other symptoms until 3rd decade
Family B: affected members were comp het for TRIM32 c.650 A > G (p.N217S) and c.1701_1703del (p.F568del) - onset of weakness in 20s
Family C: homozygous TRIM32 c.115_116insT (p.C39LfsX17) mutation seen in affected members - onset of muscle weakness in 3rd / 4th decade of life
Segregation studies showed that available healthy family members were WT or heterozygous for TRIM32 variants.

PMID: 37217920 Guan et al., 2023
Proband II1 - Chinese woman, 30yo, presented with fatigue and muscle weakness during pregnancy - diagnosed with LGMD; onset around 24yrs; muscle biopsy showed myopathic features; compound het for TRIM32 variant c.1700A > G, p.H567R & 43 kb deletion (results in removal of whole TRIM32 as well as a portion of ASTN2 gene - not linked to disease in OMIM; Method: WGS + Sanger; parents healthy het

PMID: 40017290 Caputo & Schoser, 2024 - case follow up for PMID: 15786463
Case 1 - boy with muscle weakness and pain after exercise, first noted at 6yrs; the weakness was progressive, and he was wheelchair bound at age 38yrs, respiratory insufficiency was present at age 44yrs; homozygous for TRIM32 p.D487N variant
Case 2 - younger brother of Case 1, first presented at 32 years with exercise induced muscle pain; progressive muscle weakness led to wheelchair use, respiratory symptoms noted at age 52yrs; elevated CK; homozygous for TRIM32 p.D487N variant
Congenital myopathy v7.61 CASQ1 Arina Puzriakova changed review comment from: Phenotype is not within the scope of the panel - the disorder associated with CASQ1 variants is characterised by adult-onset myalgia, proximal weakness, fatigue, and elevated serum creatine kinase. Although there is some phenotypic overlap other congenital myopathies, there are no congenital reports associated with this gene, and even childhood onset cases are very rare. Therefore maintaining Red rating on this panel.; to: Phenotype is not within the scope of the panel - the disorder associated with CASQ1 variants is characterised by adult-onset myalgia, proximal weakness, fatigue, and elevated serum creatine kinase. The phenotype is better aligned with rhabdomyolysis panels where it is already Green or tagged for promotion. Although there is some phenotypic overlap other congenital myopathies, there are no congenital reports associated with this gene, and even childhood onset cases are very rare. Therefore maintaining Red rating on this panel.
Congenital myopathy v7.61 CASQ1 Arina Puzriakova edited their review of gene: CASQ1: Added comment: Phenotype is not within the scope of the panel - the disorder associated with CASQ1 variants is characterised by adult-onset myalgia, proximal weakness, fatigue, and elevated serum creatine kinase. Although there is some phenotypic overlap other congenital myopathies, there are no congenital reports associated with this gene, and even childhood onset cases are very rare. Therefore maintaining Red rating on this panel.; Changed rating: RED
Congenital myopathy v7.61 TRIM32 Ida Ertmanska reviewed gene: TRIM32: Rating: RED; Mode of pathogenicity: None; Publications: 17994549, 37217920, 40017290; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 8, OMIM:254110, autosomal recessive limb-girdle muscular dystrophy type 2H, MONDO:0009683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.61 MCOLN1 Eleanor Williams reviewed gene: MCOLN1: Rating: RED; Mode of pathogenicity: None; Publications: 33454187; Phenotypes: Mucolipidosis IV, OMIM:252650, mucolipidosis type IV, MONDO:0009653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.12 MCOLN1 Eleanor Williams changed review comment from: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248)                                                                                                          

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap.

; to: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248)                                                                                                          

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap.

Congenital muscular dystrophy v7.12 MCOLN1 Eleanor Williams Phenotypes for gene: MCOLN1 were changed from to Mucolipidosis IV, OMIM:252650; mucolipidosis type IV, MONDO:0009653
Congenital muscular dystrophy v7.11 MCOLN1 Eleanor Williams Publications for gene: MCOLN1 were set to
Congenital muscular dystrophy v7.10 MCOLN1 Eleanor Williams Classified gene: MCOLN1 as Red List (low evidence)
Congenital muscular dystrophy v7.10 MCOLN1 Eleanor Williams Gene: mcoln1 has been classified as Red List (Low Evidence).
Congenital muscular dystrophy v7.9 MCOLN1 Eleanor Williams Deleted their comment
Congenital muscular dystrophy v7.9 MCOLN1 Eleanor Williams changed review comment from: Mucolipidosis type IV, is a rare autosomal recessive lysosomal storage disease resulting from loss-of function mutations in the MCOLN1 gene (from PMID: 32604955 )                                                                                                            

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition
of the clinical overlap.

PMID: 32604955 Jezela-Stanek et al 2020; to: Mucolipidosis IV (ML4) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities (OMIM:605248)                                                                                                          

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition of the clinical overlap.

Congenital muscular dystrophy v7.9 MCOLN1 Eleanor Williams commented on gene: MCOLN1: Mucolipidosis type IV, is a rare autosomal recessive lysosomal storage disease resulting from loss-of function mutations in the MCOLN1 gene (from PMID: 32604955 )                                                                                                            

PMID: 33454187 Zambon et al 2021 - Bangladeshi boy with consanguineous parents presented with delayed motor milestones, hypotonia and an elevated creatine kinase (CK) at 2.5 yo. Electromyography revealed a myopathy with no evidence of peripheral neuropathy. Muscle biopsy showed evidence of lysosomal storage with mild degeneration/regeneration, but no overt dystrophic changes. WGS found a homozygous null variant in MCOLN1 c.514C>T; p.(Arg172Ter). Both parents were heterozygous carriers of this variant.
The authors note that MCOLN1 analysis may not be included in congenital muscular dystrophy gene panels due to the lack of recognition
of the clinical overlap.

PMID: 32604955 Jezela-Stanek et al 2020
Congenital muscular dystrophy v7.9 MCOLN1 Eleanor Williams reviewed gene: MCOLN1: Rating: RED; Mode of pathogenicity: None; Publications: 33454187; Phenotypes: Mucolipidosis IV, OMIM:252650, mucolipidosis type IV, MONDO:0009653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic diabetes v3.25 ISCA-37432-Loss Eleanor Williams Mode of inheritance for Region: ISCA-37432-Loss was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic diabetes v3.24 ISCA-37432-Loss Eleanor Williams Publications for Region: ISCA-37432-Loss were set to
Monogenic diabetes v3.23 ISCA-37432-Loss Eleanor Williams Phenotypes for Region: ISCA-37432-Loss were changed from 614527; utero-vaginal atresia; RCAD syndrome; Schizophrenia; Chromosome 17q12 deletion syndrome; delayed development, intellectual disability; global developmental delay; Autism Spectrum Disorder; Renal cysts and diabetes syndrome; Mayer-Rokitansky-Kster-Hauser (MRKH) syndrome in females to 614527; utero-vaginal atresia; RCAD syndrome; Schizophrenia; Chromosome 17q12 deletion syndrome; delayed development, intellectual disability; global developmental delay; Autism Spectrum Disorder; Renal cysts and diabetes syndrome; Mayer-Rokitansky-Kster-Hauser (MRKH) syndrome in females; Type 2 diabetes mellitus, OMIM:125853; Renal cysts and diabetes syndrome, OMIM:137920
Intellectual disability v10.19 RDH11 Eleanor Williams Phenotypes for gene: RDH11 were changed from ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118 to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118; retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, MONDO:0014495
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.6 RDH11 Eleanor Williams Phenotypes for gene: RDH11 were changed from ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118 to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118; retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, MONDO:0014495
Malformations of cortical development v8.4 RDH11 Eleanor Williams Phenotypes for gene: RDH11 were changed from ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118 to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118; retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, MONDO:0014495
Bilateral congenital or childhood onset cataracts v8.4 RDH11 Eleanor Williams Phenotypes for gene: RDH11 were changed from ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118 to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118; retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, MONDO:0014495
Retinal disorders v9.5 RDH11 Eleanor Williams Phenotypes for gene: RDH11 were changed from ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118 to ?Retinal dystrophy, juvenile cataracts, and short stature syndrome, OMIM:616108; Neurodevelopmental delay, HP:0012758; Juvenile cataract, HP:0001118; retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, MONDO:0014495
Pituitary hormone deficiency v4.9 GHR Eleanor Williams Phenotypes for gene: GHR were changed from Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271; Increased responsiveness to growth hormone, OMIM:604271 to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271; I Laron syndrome, MONDO:0009877; short stature due to partial GHR deficiency, MONDO:0011420 ncreased responsiveness to growth hormone, OMIM:604271
Monogenic short stature v2.7 GHR Eleanor Williams Phenotypes for gene: GHR were changed from Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271 to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271; Laron syndrome, MONDO:0009877; short stature due to partial GHR deficiency, MONDO:0011420
Fetal anomalies v7.13 FAM92A Eleanor Williams Entity copied from Limb disorders v8.9
Fetal anomalies v7.13 FAM92A Eleanor Williams gene: FAM92A was added
gene: FAM92A was added to Fetal anomalies. Sources: Literature,Expert Review Amber
new-gene-name, Q2_26_promote_green tags were added to gene: FAM92A.
Mode of inheritance for gene: FAM92A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM92A were set to 30395363; 38853702
Phenotypes for gene: FAM92A were set to ?Polydactyly, postaxial, type A9, OMIM:618219; polydactyly, postaxial, type A9, MONDO:0032603
Monogenic hearing loss v6.23 CLIC5 Eleanor Williams Phenotypes for gene: CLIC5 were changed from Deafness, autosomal recessive 103, OMIM:616042 to Deafness, autosomal recessive 103, OMIM:616042; autosomal recessive nonsyndromic hearing loss 103, MONDO:0014469
Early onset or syndromic epilepsy v9.9 KCNJ4 Eleanor Williams Phenotypes for gene: KCNJ4 were changed from Epileptic encephalopathy; Epilepsy; Developmental delay. to Epileptic encephalopathy; Epilepsy; Developmental delay. epilepsy, MONDO:0005027
Likely inborn error of metabolism v9.11 FOCAD Ida Ertmanska Classified gene: FOCAD as Amber List (moderate evidence)
Likely inborn error of metabolism v9.11 FOCAD Ida Ertmanska Gene: focad has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v9.10 FOCAD Ida Ertmanska commented on gene: FOCAD: Comment on list classification: There are now numerous individuals reported with biallelic FOCAD variants and severe congenital liver disease. Liver cirrhosis in the neonatal period was a consistent finding. 86% of patients also had metabolic anomalies (e.g., steatosis, increased glycogen content, iron overload). Hence, this gene should be promoted to Green at the next GMS update. This association is tagged for expert review regarding phenotypic fit for the panel, as the metabolic anomalies are quite variable. Inclusion on this panel would also ensure inclusion on R27 Paediatric disorders, which covers more syndromic presentations.
Likely inborn error of metabolism v9.10 FOCAD Ida Ertmanska changed review comment from: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies (85.7%), hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature; to: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies (85.7% - e.g., steatosis, increased glycogen content, iron overload), hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature
Likely inborn error of metabolism v9.10 FOCAD Ida Ertmanska gene: FOCAD was added
gene: FOCAD was added to Likely inborn error of metabolism. Sources: Literature
Q2_26_promote_green, Q2_26_expert_review tags were added to gene: FOCAD.
Mode of inheritance for gene: FOCAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOCAD were set to 35864190; 40662096; 41189834; 41608453
Phenotypes for gene: FOCAD were set to Liver disease, severe congenital, OMIM:619991; liver disease, severe congenital, MONDO:0859273
Review for gene: FOCAD was set to GREEN
Added comment: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies (85.7%), hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.5 DYSF Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Although there is sufficient evidence available for the association of biallelic DYSF variants to AR limb-girdle muscular dystrophy, there is only one family reported with monoallelic variants. Hence, the gene should remain rated green with 'BIALLELIC, autosomal or pseudoautosomal' MOI.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.5 DYSF Achchuthan Shanmugasundram Mode of inheritance for gene: DYSF was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.4 DYSF Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Biallelic variants in DYSF gene are associated with relevant phenotypes in OMIM (MIMs #253601, #254130 & #606768) and the records were last accessed 11 June 2026.

Biallelic DYSF variants are also associated with AR limb-girdle muscular dystrophy with 'Definitive' rating by the Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004715).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.4 DYSF Achchuthan Shanmugasundram Phenotypes for gene: DYSF were changed from Muscular dystrophy, limb-girdle, type 2B, 253601Myopathy, distal, with anterior tibial onset, 606768Miyoshi muscular dystrophy 1, 254130; Limb-Girdle Muscular Dystrophy, Recessive; Limb-girdle muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601; Miyoshi muscular dystrophy 1, OMIM:254130; Myopathy, distal, with anterior tibial onset, OMIM:606768
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.3 DYSF Achchuthan Shanmugasundram reviewed gene: DYSF: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601, Miyoshi muscular dystrophy 1, OMIM:254130, Myopathy, distal, with anterior tibial onset, OMIM:606768; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.3 SPTAN1 Achchuthan Shanmugasundram changed review comment from: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. All affected participants presented with early childhood onset of gait and foot abnormalities. In general, participants showed stable or very slowly progressive (9/20) distal muscle weakness involving the foot (19/20) and toe extensors (15/20).

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.

The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).
Sources: Literature; to: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. All affected participants presented with early childhood onset of gait and foot abnormalities. In general, participants showed stable or very slowly progressive (9/20) distal muscle weakness involving the foot (19/20) and toe extensors (15/20). Muscle biopsy revealed myopathic changes in seven patients.

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.

The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).
Sources: Literature
Congenital myopathy v7.61 SPTAN1 Achchuthan Shanmugasundram changed review comment from: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. Individuals presented with gait disturbance and foot abnormalities, including pes cavus and distal arthrogryposis. Muscle biopsy revealed myopathic changes in seven patients.

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.

The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).; to: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. All affected participants presented with early childhood onset of gait and foot abnormalities. In general, participants showed stable or very slowly progressive (9/20) distal muscle weakness involving the foot (19/20) and toe extensors (15/20). Muscle biopsy revealed myopathic changes in seven patients.

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.

The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.3 SPTAN1 Achchuthan Shanmugasundram changed review comment from: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. Individuals presented with gait disturbance and foot abnormalities, including pes cavus and distal arthrogryposis. Muscle biopsy revealed myopathic changes in seven patients.

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.

The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).
Sources: Literature; to: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. All affected participants presented with early childhood onset of gait and foot abnormalities. In general, participants showed stable or very slowly progressive (9/20) distal muscle weakness involving the foot (19/20) and toe extensors (15/20).

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.

The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).
Sources: Literature
Cytopenia - NOT Fanconi anaemia v5.2 ACKR1 Carl Fratter reviewed gene: ACKR1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37008163; Phenotypes: OMIM 611862 ACKR1/DARC-associated neutropenia (ADAN); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary neuropathy or pain disorder v8.4 LAS1L Karen Stals reviewed gene: LAS1L: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35627110, PMID: 24647030; Phenotypes: SMARD-like, respiratory distress, apnoea, hypotonia; 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 v10.18 SF3B1 Karen Stals gene: SF3B1 was added
gene: SF3B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SF3B1 were set to PMID: 41577671
Phenotypes for gene: SF3B1 were set to Neurodevelopmental disorder; language impairment; developmental delay; seizures; dysmorphism; congenital anomalies
Review for gene: SF3B1 was set to GREEN
gene: SF3B1 was marked as current diagnostic
Added comment: PMID: 41577671 report 26 individuals with a neurodevelopmental disorder and a SF3B1 heterozygous variant - loss of function (n = 9) and missense variants (n = 17) (mostly de novo), authors propose a more severe phenotype associated with missense variants
Sources: Literature
Congenital myopathy v7.61 HNRNPA1 Achchuthan Shanmugasundram Classified gene: HNRNPA1 as Red List (low evidence)
Congenital myopathy v7.61 HNRNPA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one patient reported so far with early-onset myopathy and monoallelic HNRNPA1 variants. Hence, this gene should remain red with the current evidence.
Congenital myopathy v7.61 HNRNPA1 Achchuthan Shanmugasundram Gene: hnrnpa1 has been classified as Red List (Low Evidence).
Congenital myopathy v7.60 HNRNPA1 Achchuthan Shanmugasundram Phenotypes for gene: HNRNPA1 were changed from ?Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 to ?Myopathy, distal, 3, OMIM:610099; ?Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424
Congenital myopathy v7.59 HNRNPA1 Achchuthan Shanmugasundram Publications for gene: HNRNPA1 were set to
Congenital myopathy v7.58 HNRNPA1 Achchuthan Shanmugasundram edited their review of gene: HNRNPA1: Added comment: PMID:39121134 (2024) reported a female patient with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Between 3 and 5 years, she developed progressive generalised muscle weakness and atrophy affecting her extremities, limb girdle and trunk muscles accompanied by worsening of gait instability, myopathic facies and difficulties chewing and swallowing. She was identified with a 85-bp deletion in HNRNPA1 gene (c.684_751 + 17del).; Changed rating: RED; Changed phenotypes to: ?Myopathy, distal, 3, OMIM:610099, ?Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424
Congenital myopathy v7.58 HNRNPA1 Achchuthan Shanmugasundram reviewed gene: HNRNPA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39121134; Phenotypes: ?Myopathy, distal, 3 , ?Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.58 CCDC78 Achchuthan Shanmugasundram changed review comment from: PMID:39273074 (2024) reported a 52-year-old male patient experiencing myalgias, calf cramps, and bilateral calf
hypertrophy since the age of about 40 and identified with a heterozygous nonsense variant in CCDC78 gene (p.Trp402Ter). His 19-year-old daughter carries the same variant but is largely asymptomatic aside from bilateral calf hypertrophy and patent foramen ovale. Functional evidence suggests loss-of-function mechanism.

This gene has been associated with MIM #614807 in OMIM (last accessed 10 June 2026) and in Gene2Phenotype (with 'limited' rating on the DD panel.; to: PMID:39273074 (2024) reported a 52-year-old male patient experiencing myalgias, calf cramps, and bilateral calf
hypertrophy since the age of about 40 and identified with a heterozygous nonsense variant in CCDC78 gene (p.Trp402Ter). His 19-year-old daughter carries the same variant but is largely asymptomatic aside from bilateral calf hypertrophy and patent foramen ovale. Functional evidence suggests loss-of-function mechanism.

This gene has been associated with relevant phenotype in OMIM (MIM #614807, last accessed 10 June 2026), Gene2Phenotype (with 'limited' rating on the DD panel) and on ClinGen ('limited' rating by Congenital myopathies GCEP).
Congenital myopathy v7.58 CCDC78 Achchuthan Shanmugasundram Classified gene: CCDC78 as Amber List (moderate evidence)
Congenital myopathy v7.58 CCDC78 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only one family and functional evidence reported in support of the association with congenital myopathy. The new case reported in PMID:39273074 is an adult-onset patient with an asymptomatic daughter carrying the same nonsense variant. Another published case also showed reduced penetrance. Hence, the gene can only be rated amber with current evidence.
Congenital myopathy v7.58 CCDC78 Achchuthan Shanmugasundram Gene: ccdc78 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.57 CCDC78 Achchuthan Shanmugasundram Phenotypes for gene: CCDC78 were changed from Myopathy, centronuclear, 4, OMIM:614807 to centronuclear myopathy-4, OMIM:614807; Centronuclear myopathy 4, MONDO:0013890
Congenital myopathy v7.56 CCDC78 Achchuthan Shanmugasundram changed review comment from: PMID:39273074 (2024) reported a 52-year-old male patient experiencing myalgias, calf cramps, and bilateral calf
hypertrophy since the age of about 40 and identified with a heterozygous nonsense variant in CCDC78 gene (p.Trp402Ter). His 19-year-old daughter carries the same variant but is largely asymptomatic aside from bilateral calf hypertrophy and patent foramen ovale. Functional evidence suggests loss-of-function mechanism; to: PMID:39273074 (2024) reported a 52-year-old male patient experiencing myalgias, calf cramps, and bilateral calf
hypertrophy since the age of about 40 and identified with a heterozygous nonsense variant in CCDC78 gene (p.Trp402Ter). His 19-year-old daughter carries the same variant but is largely asymptomatic aside from bilateral calf hypertrophy and patent foramen ovale. Functional evidence suggests loss-of-function mechanism.

This gene has been associated with MIM #614807 in OMIM (last accessed 10 June 2026) and in Gene2Phenotype (with 'limited' rating on the DD panel.
Congenital myopathy v7.56 CCDC78 Achchuthan Shanmugasundram edited their review of gene: CCDC78: Changed phenotypes to: centronuclear myopathy-4, OMIM:614807, Centronuclear myopathy 4, MONDO:0013890
Congenital myopathy v7.56 CCDC78 Achchuthan Shanmugasundram Publications for gene: CCDC78 were set to 22818856; 25635128
Congenital myopathy v7.55 CCDC78 Achchuthan Shanmugasundram edited their review of gene: CCDC78: Added comment: PMID:39273074 (2024) reported a 52-year-old male patient experiencing myalgias, calf cramps, and bilateral calf
hypertrophy since the age of about 40 and identified with a heterozygous nonsense variant in CCDC78 gene (p.Trp402Ter). His 19-year-old daughter carries the same variant but is largely asymptomatic aside from bilateral calf hypertrophy and patent foramen ovale. Functional evidence suggests loss-of-function mechanism; Changed publications to: 22818856, 25635128, 39273074
Optic neuropathy v6.42 PHB Cassandra Smith gene: PHB was added
gene: PHB was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene: PHB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PHB were set to 42067999
Review for gene: PHB was set to AMBER
Added comment: 42067999: c.440C>T (p.Ser147Phe) segregating in five affected members of a three generation family. Ratios of OPA1 short and long isoforms were shifted in patients compared to controls
Sources: Literature
Possible mitochondrial disorder - nuclear genes v5.6 USMG5 Ida Ertmanska Classified gene: USMG5 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v5.6 USMG5 Ida Ertmanska Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v5.5 USMG5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: USMG5.
Possible mitochondrial disorder - nuclear genes v5.5 USMG5 Ida Ertmanska commented on gene: USMG5: 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.
Possible mitochondrial disorder - nuclear genes v5.5 USMG5 Ida Ertmanska commented on gene: USMG5: Added new-gene-name tag, new approved HGNC gene symbol for USMG5 is ATP5MK
Likely inborn error of metabolism v9.9 USMG5 Ida Ertmanska Classified gene: USMG5 as Amber List (moderate evidence)
Likely inborn error of metabolism v9.9 USMG5 Ida Ertmanska Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v9.8 USMG5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: USMG5.
Likely inborn error of metabolism v9.8 USMG5 Ida Ertmanska commented on gene: USMG5: Added new-gene-name tag, new approved HGNC gene symbol for USMG5 is ATP5MK
Likely inborn error of metabolism v9.8 USMG5 Ida Ertmanska commented on gene: USMG5: 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.
Mitochondrial disorder with complex V deficiency v3.5 USMG5 Ida Ertmanska Classified gene: USMG5 as Amber List (moderate evidence)
Mitochondrial disorder with complex V deficiency v3.5 USMG5 Ida Ertmanska Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex V deficiency v3.4 USMG5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: USMG5.
Mitochondrial disorder with complex V deficiency v3.4 USMG5 Ida Ertmanska commented on gene: USMG5: 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.
Mitochondrial disorder with complex V deficiency v3.4 USMG5 Ida Ertmanska commented on gene: USMG5: Added new-gene-name tag, new approved HGNC gene symbol for USMG5 is ATP5MK
Mitochondrial disorder with complex V deficiency v3.4 USMG5 Ida Ertmanska gene: USMG5 was added
gene: USMG5 was added to Mitochondrial disorder with complex V deficiency. Sources: Literature
new-gene-name tags were added to gene: USMG5.
Mode of inheritance for gene: USMG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USMG5 were set to 21345788; 29903433; 29917077; 30240627; 40014158
Phenotypes for gene: USMG5 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6, OMIM:618683; mitochondrial respiratory chain complex deficiency, MONDO:0000066
Review for gene: USMG5 was set to GREEN
Added comment: 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).
Sources: Literature
Possible mitochondrial disorder - nuclear genes v5.5 USMG5 Ida Ertmanska gene: USMG5 was added
gene: USMG5 was added to Possible mitochondrial disorder - nuclear genes. Sources: Literature
new-gene-name tags were added to gene: USMG5.
Mode of inheritance for gene: USMG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USMG5 were set to 21345788; 29903433; 29917077; 30240627; 40014158
Phenotypes for gene: USMG5 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6, OMIM:618683; mitochondrial respiratory chain complex deficiency, MONDO:0000066
Review for gene: USMG5 was set to GREEN
Added comment: 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).
Sources: Literature
Likely inborn error of metabolism v9.8 USMG5 Ida Ertmanska gene: USMG5 was added
gene: USMG5 was added to Likely inborn error of metabolism. Sources: Literature
new-gene-name tags were added to gene: USMG5.
Mode of inheritance for gene: USMG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USMG5 were set to 21345788; 29903433; 29917077; 30240627; 40014158
Phenotypes for gene: USMG5 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6, OMIM:618683; mitochondrial respiratory chain complex deficiency, MONDO:0000066
Review for gene: USMG5 was set to GREEN
Added comment: 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).
Sources: Literature
Mitochondrial disorders v10.8 USMG5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: USMG5.
Mitochondrial disorders v10.8 USMG5 Ida Ertmanska Classified gene: USMG5 as Amber List (moderate evidence)
Mitochondrial disorders v10.8 USMG5 Ida Ertmanska Added comment: 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.
Mitochondrial disorders v10.8 USMG5 Ida Ertmanska Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v10.7 USMG5 Ida Ertmanska Phenotypes for gene: USMG5 were changed from Autosomal recessive Leigh syndrome to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6, OMIM:618683; mitochondrial respiratory chain complex deficiency, MONDO:0000066
Mitochondrial disorders v10.6 USMG5 Ida Ertmanska Publications for gene: USMG5 were set to 29903433; 29917077; 30240627
Mitochondrial disorders v10.5 USMG5 Ida Ertmanska Mode of inheritance for gene: USMG5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v10.4 USMG5 Ida Ertmanska Tag founder-effect was removed from gene: USMG5.
Mitochondrial disorders v10.4 USMG5 Ida Ertmanska changed review comment from: PMID: 40014158 İpek et al. 2025
4 brothers affected by mitochondrial disease, aged 13-25 yrs. All 4 had istory 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: 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).
Mitochondrial disorders v10.4 USMG5 Ida Ertmanska reviewed gene: USMG5: Rating: GREEN; Mode of pathogenicity: None; Publications: 40014158; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6, OMIM:618683, mitochondrial respiratory chain complex deficiency, MONDO:0000066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v6.22 CLRN2 Ida Ertmanska changed review comment from: PMID: 39446282 Ahmad et al., 2025
Consanguineous family, 2 sibs with non-syndromic profound hearing loss, homozygous for CLRN2: c.414C>A, p.Cys138*. Seq method: WES + Sanger. Variant has 1 allele reported in gnomAD (no homozygotes). Parents both heterozygous for the variant and unaffected.

PMID: 33496845 (Vona et al 2021): Clrn2 mouse mutant, in which exon 2 has been deleted (Clrn2del629). Clrn2del629/del629 mice exhibit a severe-to-profound hearing loss affecting all frequencies tested.

The association between CLRN2 and AR nonsyndromic genetic hearing loss was classified as Moderate in ClinGen (Hearing Loss GCEP, Sept 2025).; to: PMID: 39446282 Ahmad et al., 2025
Consanguineous family, 2 sibs with non-syndromic profound hearing loss, homozygous for CLRN2: c.414C>A, p.Cys138*. Seq method: WES + Sanger. Variant has 1 allele reported in gnomAD (no homozygotes). Parents both heterozygous for the variant and unaffected.

PMID: 33496845 Vona et al 2021
Iranian family, where homozygous CLRN2: c.494C > A, p.Thr165Lys variant (expected to result in p.(Gly146Lysfs*26)) change) segregated with non-syndromic hearing loss.
Clrn2 mouse mutant, in which exon 2 has been deleted (Clrn2del629). Clrn2del629/del629 mice exhibit a severe-to-profound hearing loss affecting all frequencies tested.

The association between CLRN2 and AR nonsyndromic genetic hearing loss was classified as Moderate in ClinGen (Hearing Loss GCEP, Sept 2025).
Monogenic hearing loss v6.22 CLRN2 Ida Ertmanska Classified gene: CLRN2 as Amber List (moderate evidence)
Monogenic hearing loss v6.22 CLRN2 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated families reported with biallelic CLRN2 variants and non-syndromic hearing loss. Mouse model supports this association, as mice homozygous for a deletion in Clrn2 exhibit a severe-to-profound hearing loss. Hence, this gene can now be promoted to Green at the next update.
Monogenic hearing loss v6.22 CLRN2 Ida Ertmanska Gene: clrn2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.21 CLRN2 Ida Ertmanska changed review comment from: PMID: 39446282 Ahmad et al., 2025
Consanguineous family, 2 sibs with non-syndromic profound hearing loss, homozygous for CLRN2: c.414C>A, p.Cys138*. Seq method: WES + Sanger. Variant has 1 allele reported in gnomAD (no homozygotes). Parents both heterozygous for the variant and unaffected.

The association between CLRN2 and AR nonsyndromic genetic hearing loss was classified as Moderate in ClinGen (Hearing Loss GCEP, Sept 2025).; to: PMID: 39446282 Ahmad et al., 2025
Consanguineous family, 2 sibs with non-syndromic profound hearing loss, homozygous for CLRN2: c.414C>A, p.Cys138*. Seq method: WES + Sanger. Variant has 1 allele reported in gnomAD (no homozygotes). Parents both heterozygous for the variant and unaffected.

PMID: 33496845 (Vona et al 2021): Clrn2 mouse mutant, in which exon 2 has been deleted (Clrn2del629). Clrn2del629/del629 mice exhibit a severe-to-profound hearing loss affecting all frequencies tested.

The association between CLRN2 and AR nonsyndromic genetic hearing loss was classified as Moderate in ClinGen (Hearing Loss GCEP, Sept 2025).
Monogenic hearing loss v6.21 CLRN2 Ida Ertmanska Publications for gene: CLRN2 were set to 33496845
Monogenic hearing loss v6.20 CLRN2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CLRN2.
Monogenic hearing loss v6.20 CLRN2 Ida Ertmanska reviewed gene: CLRN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39446282; Phenotypes: Deafness, autosomal recessive 117, OMIM:619174, hearing loss, autosomal recessive 117, MONDO:0030905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.55 TUBA4A Achchuthan Shanmugasundram Classified gene: TUBA4A as Amber List (moderate evidence)
Congenital myopathy v7.55 TUBA4A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic TUBA4A variants with congenital myopathy. However, there are only three unrelated families reported with biallelic variants and myopathy and none of the cases had congenital or early-onset myopathy. Hence, the gene should be promoted to green rating on this panel in the next GMS update and the MOI should be set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Congenital myopathy v7.55 TUBA4A Achchuthan Shanmugasundram Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.54 TUBA4A Achchuthan Shanmugasundram Phenotypes for gene: TUBA4A were changed from to Congenital myopathy 26, OMIM:621225; congenital myopathy 26, MONDO:0979229
Congenital myopathy v7.53 TUBA4A Achchuthan Shanmugasundram Publications for gene: TUBA4A were set to
Congenital myopathy v7.52 TUBA4A Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: TUBA4A.
Tag Q2_26_NHS_review tag was added to gene: TUBA4A.
Congenital myopathy v7.52 TUBA4A Achchuthan Shanmugasundram reviewed gene: TUBA4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 38413182, 41678358; Phenotypes: Congenital myopathy 26, OMIM:621225, congenital myopathy 26, MONDO:0979229; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.3 SPTAN1 Achchuthan Shanmugasundram Classified gene: SPTAN1 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.3 SPTAN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic SPTAN1 variants with early-onset distal myopathy. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.3 SPTAN1 Achchuthan Shanmugasundram Gene: sptan1 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.2 SPTAN1 Achchuthan Shanmugasundram gene: SPTAN1 was added
gene: SPTAN1 was added to Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. Sources: Literature
Q2_26_promote_green tags were added to gene: SPTAN1.
Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTAN1 were set to 40023774; 40999194
Phenotypes for gene: SPTAN1 were set to distal myopathy, MONDO:0018949
Review for gene: SPTAN1 was set to GREEN
Added comment: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. Individuals presented with gait disturbance and foot abnormalities, including pes cavus and distal arthrogryposis. Muscle biopsy revealed myopathic changes in seven patients.

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.

The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).
Sources: Literature
Congenital myopathy v7.52 SPTAN1 Achchuthan Shanmugasundram changed review comment from: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. Individuals presented with gait disturbance and foot abnormalities, including pes cavus and distal arthrogryposis. Muscle biopsy revealed myopathic changes in seven patients.

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.
The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).; to: PMID:40023774 (2025) reported 20 patients from 14 families with heterozygous LoF SPTAN1 variants and early-onset distal myopathy (9x de novo and 5x dominantly inherited). The age of onset was 0-5 years in 14 patients, 6-10 in two, 11-15 in one and not reported in three. Exome sequencing detected 9 frameshift, 4 nonsense, and 1 splice-acceptor variant in SPTAN1. Individuals presented with gait disturbance and foot abnormalities, including pes cavus and distal arthrogryposis. Muscle biopsy revealed myopathic changes in seven patients.

PMID:40999194 (2026) reported a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene, identified via exome sequencing. The deletion segregated with disease in four individuals, and was non-penetrant in two. Affected individuals presented with distal weakness in lower limbs (4/4) as well as pes cavus and hammer toes (2/4) or Distal arthrogryposis (2/4). Electromyography, muscle MRI and muscle biopsy showed myopathic disease.

The deletion encompasses SPTAN1, DYNC2I2, and a part of GLE1. Authors pose that SPTAN1 deletion is responsible for disease, as DYNC2I2 and GLE1 are not predicted to be dosage sensitive. However, the effect of other genes being deleted cannot be decoupled.

SPTAN1 is not yet associated with distal myopathy in OMIM (accessed 09 June 2026).
Congenital myopathy v7.52 SPTAN1 Achchuthan Shanmugasundram Classified gene: SPTAN1 as Amber List (moderate evidence)
Congenital myopathy v7.52 SPTAN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic SPTAN1 variants with early-onset distal myopathy. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Congenital myopathy v7.52 SPTAN1 Achchuthan Shanmugasundram Gene: sptan1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.51 SPTAN1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: SPTAN1.
Tag Q2_26_NHS_review tag was added to gene: SPTAN1.
Congenital myopathy v7.51 SPTAN1 Achchuthan Shanmugasundram Phenotypes for gene: SPTAN1 were changed from to distal myopathy, MONDO:0018949
Congenital myopathy v7.50 SPTAN1 Achchuthan Shanmugasundram Publications for gene: SPTAN1 were set to
Congenital myopathy v7.49 SPTAN1 Achchuthan Shanmugasundram reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40023774, 40999194; Phenotypes: distal myopathy, MONDO:0018949; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.49 PACSIN3 Achchuthan Shanmugasundram Classified gene: PACSIN3 as Amber List (moderate evidence)
Congenital myopathy v7.49 PACSIN3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated families and functional evidence including mouse model in support of the disease association. Hence, this gene can be promoted to green rating in the next GMS update.
Congenital myopathy v7.49 PACSIN3 Achchuthan Shanmugasundram Gene: pacsin3 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.48 PACSIN3 Achchuthan Shanmugasundram Phenotypes for gene: PACSIN3 were changed from to Congenital myopathy 27, OMIM:621343; congenital myopathy 27, MONDO:0979897
Congenital myopathy v7.47 PACSIN3 Achchuthan Shanmugasundram Publications for gene: PACSIN3 were set to
Congenital myopathy v7.46 PACSIN3 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: PACSIN3.
Tag Q2_26_NHS_review tag was added to gene: PACSIN3.
Congenital myopathy v7.46 PACSIN3 Achchuthan Shanmugasundram changed review comment from: PMID:38637313 (2024) reported three individuals from two unrelated families presenting with childhood-onset myopathy with hyperCKaemia. They were identified with either compound heterozygous or homozygous loss-of-function variants in PACSIN3 gene via exome sequencing and confirmed by Sanger sequencing (Family 1: c.270_277del, p.Leu91AlafsTer15 and c.609_610del, p(Lys203AsnfsTer4; Family 2: c.592G>T, p.Glu198Ter), which segregated with the disorder in the two families. Ultrastructural studies in muscle tissue derived from Individual 1 showed accumulation of membranous tubules, some of which were arranged in tubular aggregates.

PMID:29202928 (2017) reported evidence from Syndapin III knockout mice, which are viable, fertile, and developed without obvious impairments under normal conditions. But, their muscle cells showed a severe reduction in caveolar invaginations without loss of caveolin3 or cavin1 from the plasma membrane . Upon physical exercise, the knockout skeletal muscles exhibited pathological features including widened fibre calibre, detached nuclei, inflammation, and necrosis - phenocopying human myopathies associated with CAV3 mutations.; to: PMID:38637313 (2024) reported three individuals from two unrelated families presenting with childhood-onset myopathy with hyperCKaemia. They were identified with either compound heterozygous or homozygous loss-of-function variants in PACSIN3 gene via exome sequencing and confirmed by Sanger sequencing (Family 1: c.270_277del, p.Leu91AlafsTer15 and c.609_610del, p(Lys203AsnfsTer4; Family 2: c.592G>T, p.Glu198Ter), which segregated with the disorder in the two families. Ultrastructural studies in muscle tissue derived from Individual 1 showed accumulation of membranous tubules, some of which were arranged in tubular aggregates.

PMID:29202928 (2017) reported evidence from Syndapin III knockout mice, which are viable, fertile, and developed without obvious impairments under normal conditions. But, their muscle cells showed a severe reduction in caveolar invaginations without loss of caveolin3 or cavin1 from the plasma membrane . Upon physical exercise, the knockout skeletal muscles exhibited pathological features including widened fibre calibre, detached nuclei, inflammation, and necrosis - phenocopying human myopathies associated with CAV3 mutations.

This gene has been associated with relevant phenotypes in both OMIM (MIM # 621343, last accessed 09 June 2026) and Gene2Phenotype (with 'moderate' rating on the DD panel).
Congenital myopathy v7.46 PACSIN3 Achchuthan Shanmugasundram reviewed gene: PACSIN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29202928, 38637313; Phenotypes: Congenital myopathy 27, OMIM:621343, congenital myopathy 27, MONDO:0979897; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v10.10 CNTN1 Arina Puzriakova Phenotypes for gene: CNTN1 were changed from Myopathy, congenital, Compton-North, OMIM:612540 to Congenital myopathy 12, OMIM:612540
Fetal anomalies v7.12 CNTN1 Arina Puzriakova Phenotypes for gene: CNTN1 were changed from Myopathy, congenital, Compton-North, OMIM:612540 to Congenital myopathy 12, OMIM:612540
Monogenic hearing loss v6.20 CD164 Ida Ertmanska Classified gene: CD164 as Amber List (moderate evidence)
Monogenic hearing loss v6.20 CD164 Ida Ertmanska Added comment: 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.
Monogenic hearing loss v6.20 CD164 Ida Ertmanska Gene: cd164 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.19 CD164 Ida Ertmanska Phenotypes for gene: CD164 were changed from ?Deafness, autosomal dominant 66 616969 to ?Deafness, autosomal dominant 66, OMIM:616969; autosomal dominant nonsyndromic hearing loss 66, MONDO:0014854
Monogenic hearing loss v6.18 CD164 Ida Ertmanska Publications for gene: CD164 were set to 26197441
Monogenic hearing loss v6.17 CD164 Ida Ertmanska Mode of inheritance for gene: CD164 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v6.16 CD164 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CD164.
Monogenic hearing loss v6.16 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.; 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.

The assocation between CD164 and autosomal dominant nonsyndromic hearing loss has been classified as Moderate by ClinGen Hearing Loss GCEP in 2024.
Monogenic hearing loss v6.16 CD164 Ida Ertmanska reviewed gene: CD164: Rating: GREEN; Mode of pathogenicity: None; Publications: 26197441, 35254497, 36454368; Phenotypes: ?Deafness, autosomal dominant 66, OMIM:616969; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v9.14 NPR2 Arina Puzriakova Phenotypes for gene: NPR2 were changed from Acromesomelic dysplasia, Maroteaux type 602875; Short stature with nonspecific skeletal abnormalities 616255; Epiphyseal chondrodysplasia, Miura type 615923 to Acromesomelic dysplasia 1, Maroteaux type, OMIM:602875; Epiphyseal chondrodysplasia, Miura type, OMIM:615923; Short stature with nonspecific skeletal abnormalities, OMIM:616255
Multiple monogenic benign skin tumours v2.6 NOTCH3 Ida Ertmanska edited their review of gene: NOTCH3: Changed rating: AMBER
Multiple monogenic benign skin tumours v2.6 NOTCH3 Ida Ertmanska changed review comment from: PMID: 36788105 Iwamura et al., 2023
NOTCH3 mutations were identified in 9 of the 41 pericytic tumors investigated, including 4 myopericytomas, 1 myopericytomatosis, 3 angioleiomyomas, and 1 glomus tumor. A wide variety of NOTCH3 mutations was found, including A1480S, A1480T, D1481N, G1482S, T1490A, E1491K, G1494S, and V1512A.

PMID: 41263773 Ungureanu et al., 2025
Report of two cases of myofibroma: one aggressive case with central nervous system involvement in a newborn, exhibiting a monophasic morphology, and a second, subcutaneous case in an adult.
Case 1 - internal tandem duplication (ITD) of exon 26 L1614_V1629 of the NOTCH3 gene
Case 2 - ITD of NOTCH3 exon 27 L1644_P1645ins16; to: PMID: 36788105 Iwamura et al., 2023
NOTCH3 mutations were identified in 9 of the 41 pericytic tumors investigated, including 4 myopericytomas, 1 myopericytomatosis, 3 angioleiomyomas, and 1 glomus tumor. A wide variety of NOTCH3 mutations was found, including A1480S, A1480T, D1481N, G1482S, T1490A, E1491K, G1494S, and V1512A.

PMID: 41263773 Ungureanu et al., 2025
Report of two somatic cases of myofibroma: one aggressive case with central nervous system involvement in a newborn, exhibiting a monophasic morphology, and a second, subcutaneous case in an adult.
Case 1 - internal tandem duplication (ITD) of exon 26 L1614_V1629 of the NOTCH3 gene
Case 2 - ITD of NOTCH3 exon 27 L1644_P1645ins16
Multiple monogenic benign skin tumours v2.6 NOTCH3 Ida Ertmanska reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36788105, 41263773; Phenotypes: ?Myofibromatosis, infantile 2 , OMIM:615293; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - narrow panel v8.3 NOTCH3 Ida Ertmanska Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295; Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1, OMIM:125310 to Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295
Adult onset neurodegenerative disorder v9.2 NOTCH3 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: NOTCH3.
Adult onset neurodegenerative disorder v9.2 NOTCH3 Ida Ertmanska commented on gene: NOTCH3: Comment on mode of inheritance: Both monoallelic and biallelic variants (cysteine-involving missense variants) are known to cause CADASIL spectrum phenotype, which in many cases includes neurodegeneration leading to dementia. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Adult onset neurodegenerative disorder v9.2 NOTCH3 Ida Ertmanska reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295, Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, MONDO:0000914; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v9.2 NOTCH3 Ida Ertmanska Deleted their review
Adult onset neurodegenerative disorder v9.2 NOTCH3 Ida Ertmanska Deleted their comment
Adult onset neurodegenerative disorder v9.2 NOTCH3 Ida Ertmanska Deleted their comment
Adult onset neurodegenerative disorder v9.2 NOTCH3 Ida Ertmanska Tag Q2_26_MOI was removed from gene: NOTCH3.
Adult onset neurodegenerative disorder v9.2 NOTCH3 Ida Ertmanska Publications for gene: NOTCH3 were set to 31960911
Adult onset neurodegenerative disorder v9.1 NOTCH3 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: NOTCH3.
Adult onset neurodegenerative disorder v9.1 NOTCH3 Ida Ertmanska commented on gene: NOTCH3: Comment on mode of inheritance: Both monoallelic and biallelic variants (cysteine-involving missense variants) are known to cause CADASIL spectrum phenotype. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Adult onset neurodegenerative disorder v9.1 NOTCH3 Ida Ertmanska reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295, Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, MONDO:0000914; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
CADASIL v1.7 NOTCH3 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: NOTCH3.
CADASIL v1.7 NOTCH3 Ida Ertmanska commented on gene: NOTCH3: Comment on mode of inheritance: Both monoallelic and biallelic variants (cysteine-involving missense variants) are known to cause CADASIL spectrum phenotype. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
CADASIL v1.7 NOTCH3 Ida Ertmanska edited their review of gene: NOTCH3: Added comment: Review by Achchuthan Shanmugasundram (Genomics England Curator), copied from Adult onset leukodystrophy:

PMID: 39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss.

Confluent deep, subcortical white matter lesions were reported in 21 patients with biallelic cysteine-involving missense variants. In addition, white matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL.; Changed rating: GREEN; Changed publications to: 39191170; Changed phenotypes to: Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295, Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, MONDO:0000914; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
CADASIL v1.7 NOTCH3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 9th June 2026.
CADASIL v1.7 NOTCH3 Ida Ertmanska Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310; cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, MONDO:0000914 to Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295; Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310; cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, MONDO:0000914
White matter disorders and cerebral calcification - narrow panel v8.2 NOTCH3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 9th June 2026.
White matter disorders and cerebral calcification - narrow panel v8.2 NOTCH3 Ida Ertmanska Phenotypes for gene: NOTCH3 were changed from neurodevelopmental disorder, MONDO:0700092; leukodystrophy, MONDO:0019046 to Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295; Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
Adult onset leukodystrophy v7.2 NOTCH3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 9th June 2026.
Adult onset leukodystrophy v7.2 NOTCH3 Ida Ertmanska Phenotypes for gene: NOTCH3 were changed from Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, OMIM:125310; neurodevelopmental disorder, MONDO:0700092; leukodystrophy, MONDO:0019046 to Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, OMIM:621295; Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1, OMIM:125310
Iron metabolism disorders - NOT common HFE mutations v4.2 FTL Ida Ertmanska commented on gene: FTL: There are 4 unrelated cases with biallelic FTL variants: 2 Hereditary hyperferritinemia cataract syndrome (HHCS) cases with 5' UTR variants, 1 case with homozygous nonsense variants and a neurological phenotype, and 1 case with a homozygous missense variant - subclinical apart from fatigue. While there is a phenotypic variability here, all the recessive conditions stem from an underlying iron metabolism disorder. Hence, the MOI should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.
Iron metabolism disorders - NOT common HFE mutations v4.2 FTL Arina Puzriakova Phenotypes for gene: FTL were changed from Hyperferritinemia-cataract syndrome OIMM:600886; L-ferritin deficiency, dominant and recessive OMIM:615604; Neurodegeneration with brain iron accumulation 3 OMIM:606159 to Hyperferritinemia-cataract syndrome, OMIM:600886; L-ferritin deficiency, dominant and recessive, OMIM:615604; Neurodegeneration with brain iron accumulation 3, OMIM:606159
Bilateral congenital or childhood onset cataracts v8.3 FTL Arina Puzriakova Phenotypes for gene: FTL were changed from Hyperferritinemia-cataract syndrome, 600886; Hyperferritinemia Cataract Syndrome; HEREDITARY HYPERFERRITINEMIA-CATARACT SYNDROME to Hyperferritinemia-cataract syndrome, OMIM:600886; L-ferritin deficiency, dominant and recessive, OMIM:615604
Bilateral congenital or childhood onset cataracts v8.2 FTL Arina Puzriakova Publications for gene: FTL were set to
Hereditary neuropathy or pain disorder v8.4 DHTKD1 James Polke reviewed gene: DHTKD1: Rating: RED; Mode of pathogenicity: None; Publications: 34571524, 29661920, 28902413; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v9.13 GHR Ida Ertmanska reviewed gene: GHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 21900382, 33912130, 34453441, 36943306, 37474955; Phenotypes: Laron dwarfism, OMIM:262500, Growth hormone insensitivity, partial, OMIM:604271; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Pituitary hormone deficiency v4.8 GHR Ida Ertmanska Publications for gene: GHR were set to
Pituitary hormone deficiency v4.7 GHR Ida Ertmanska Tag Q2_26_MOI tag was added to gene: GHR.
Pituitary hormone deficiency v4.7 GHR Ida Ertmanska commented on gene: GHR: Comment on mode of inheritance: There are numerous individuals reported with biallelic GHR variants and Laron dwarfism - proportionate severe short stature (often -5 to -12 SDS) stemming from primary resistance to growth hormone. In addition, there are at least 6 unrelated probands with heterozygous GHR variants that have milder presentation than Laron dwarfism, yet with short stature more severe than -3 SD. There is good evidence of short stature segregating with GHR variants in a dominant manner in these families, though with variable severity. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Pituitary hormone deficiency v4.7 GHR Ida Ertmanska reviewed gene: GHR: Rating: GREEN; Mode of pathogenicity: None; Publications: 21900382, 33912130, 34453441, 36943306, 37474955; Phenotypes: Laron dwarfism, OMIM:262500, Growth hormone insensitivity, partial, OMIM:604271; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Monogenic short stature v2.6 GHR Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 8th June 2026.
Monogenic short stature v2.6 GHR Ida Ertmanska Phenotypes for gene: GHR were changed from Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271 to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271
Monogenic short stature v2.5 GHR Ida Ertmanska Phenotypes for gene: GHR were changed from Laron dwarfism, OMIM:262500 to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271
Monogenic short stature v2.4 GHR Ida Ertmanska Publications for gene: GHR were set to
Monogenic short stature v2.3 GHR Ida Ertmanska Tag Q2_26_MOI tag was added to gene: GHR.
Monogenic short stature v2.3 GHR Ida Ertmanska commented on gene: GHR: Comment on mode of inheritance: There are numerous individuals reported with biallelic GHR variants and Laron dwarfism - proportionate severe short stature (often -5 to -12 SDS) stemming from primary resistance to growth hormone. In addition, there are at least 6 unrelated probands with heterozygous GHR variants that have milder presentation than Laron dwarfism, yet with short stature more severe than -3 SD. There is good evidence of short stature segregating with GHR variants in a dominant manner in these families, though with variable severity. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Monogenic short stature v2.3 GHR Ida Ertmanska edited their review of gene: GHR: Changed publications to: 21900382, 33912130, 34453441, 36943306, 37474955
Monogenic short stature v2.3 GHR Ida Ertmanska changed review comment from: RECESSIVE LARON DWARFISM:
PMID: 37474955 Bitarafan et al., 2023
Report of 3 sibs from a consanguineous Iranian family with Laron dwarfism. WES revealed the affected children were homozygous for GHR variant NM_000163.5; c.610 T>A, p.(Trp204Arg). Proband, 32yo male, had height of 146cm (-3.3 SDS) and skeletal maturity estimated at 13 years of age. Recurrent kidney stones also noted. Affected sibs' heights were -2.6 SDS and -4.6 SDS. 3 healthy brothers heterozygous for the variant had normal height; father's height was -2.1SDS, and mother's height -1.7SDS. Authors pose this variability comes from compensatory mechanisms.

PMID: 33912130 Li et al., 2021
4 male Chinese patients with proportionate short stature (height SDS of -5.49, -6.71, -3.95, and -2.80 at 3-14 yrs old). 3/4 patients had higher growth hormone (GH) levels than normal, and 3/4 cases had IGF-1 levels lower than the norm ( 4th case was borderline but very low). All 4 had bone age retardation (median 18 months delay), and there were no signs of pituitary abnormalities on MRI.
P3 had a heterozygous STOP-gain mutation (and most severe phenotype, height -6.71 SDS), P1 and P2 had biallelic missense mutations, and P4 harboured one missense and one frameshift variant, both inherited from unaffected parents. Caveat: only exons 2-10 of GHR were sequenced.

PMID: 34453441 Cottrell et al., 2021
2 kindreds of shared Italian ancestry (both from Campania). Homozygous deep intronic variant in GHR g.5:42700940T > G, c.618+836T>G results in loss of GHR function consistent with a severe GHI phenotype.

DOMINANT GH INSENSITIVITY:
PMID: 36943306 Andrews et al., 2023
Report of novel heterozygous GHR variants were identified in 2 unrelated patients with 'non-classical' GHI - posed to be dominant negative.
P1 - c.876-15T > G (rs199960137); height at 16.5 yrs was 153cm (−3.2 SDS); also presented with relative macrocephaly, disproportionate short stature borderline mesomelic shortening on skeletal survey
P2 - het de novo variant c.902T > G, p.V301G; height at 14.6 yrs was 155cm (-2.7 SDS); no dysmorphic features; IGF1 deficiency (SDS −3.0)
Seq method: NGS short stature panel. Milder presentation delayed diagnosis and prevented treatment in these patients.

PMID: 31883394 Rughani et al., 2020
Young male Caucasian child with short stature, found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP; heterozygous for c.800G > A, p.Trp267* in GHR. At 23 months of age, his height was was 75.8 cm (−3.6 SDS). Method: GHR gene sequencing. Variant inherited from the patient's mother, whose height was 152 cm (−1.7 SDS).

PMID: 29188236 Vairamani et al., 2017
Report of three families with dominant-negative heterozygous mutations in the intracellular domain of GHR, causing a nonclassical GHI phenotype. Detected variants: c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C.
P1 - female with height 109.9 cm (−3.89 SD) at 8yrs 8 mo; low IGF1; variant inherited from a father with short stature (-2SD), strong family history of short stature (-2 to -4.4 SD) on father's side; WES
P2 - Spanish boy with height of 88.8 cm (−3.1 SD) at 3.8yrs; serum IGF-I was low normal; parents height: father -1.8SD and mother −2.46 SD) - variant inherited from the mother; targeted Sanger seq of GHR
P3 - 12yo female with short stature: 119.6 cm, −4.30 SD; high basal GH and low IGF-1 noted; father, mother, and grandfather all of very short stature (-3.6 to -4.3 SD). Variant in GHR inherited from the mother; targeted Sanger seq of GHR
P4 - Pakistani proband; height of 85.4 cm (−4.17 SD) at 4 yrs old; low IGF-I of 16 ng/mL (normal, 54 to 178); carried de novo GHR c.899dupC mutation and p.R229H missense variant inherited from the mother

GHR is associated with AR Laron dwarfism, OMIM:262500 and AD Growth hormone insensitivity, partial, OMIM:604271 in OMIM (accessed 8th June 2026).; to: RECESSIVE LARON DWARFISM:
PMID: 37474955 Bitarafan et al., 2023
Report of 3 sibs from a consanguineous Iranian family with Laron dwarfism. WES revealed the affected children were homozygous for GHR variant NM_000163.5; c.610 T>A, p.(Trp204Arg). Proband, 32yo male, had height of 146cm (-3.3 SDS) and skeletal maturity estimated at 13 years of age. Recurrent kidney stones also noted. Affected sibs' heights were -2.6 SDS and -4.6 SDS. 3 healthy brothers heterozygous for the variant had normal height; father's height was -2.1SDS, and mother's height -1.7SDS. Authors pose this variability comes from compensatory mechanisms.

PMID: 33912130 Li et al., 2021
4 male Chinese patients with proportionate short stature (height SDS of -5.49, -6.71, -3.95, and -2.80 at 3-14 yrs old). 3/4 patients had higher growth hormone (GH) levels than normal, and 3/4 cases had IGF-1 levels lower than the norm ( 4th case was borderline but very low). All 4 had bone age retardation (median 18 months delay), and there were no signs of pituitary abnormalities on MRI.
P3 had a heterozygous STOP-gain mutation (and most severe phenotype, height -6.71 SDS), P1 and P2 had biallelic missense mutations, and P4 harboured one missense and one frameshift variant, both inherited from unaffected parents. Caveat: only exons 2-10 of GHR were sequenced.

PMID: 34453441 Cottrell et al., 2021
2 kindreds of shared Italian ancestry (both from Campania). Homozygous deep intronic variant in GHR g.5:42700940T > G, c.618+836T>G results in loss of GHR function consistent with a severe GHI phenotype.

DOMINANT GH INSENSITIVITY:
PMID: 36943306 Andrews et al., 2023
Report of novel heterozygous GHR variants were identified in 2 unrelated patients with 'non-classical' GHI - posed to be dominant negative.
P1 - c.876-15T > G (rs199960137); height at 16.5 yrs was 153cm (−3.2 SDS); also presented with relative macrocephaly, disproportionate short stature borderline mesomelic shortening on skeletal survey
P2 - het de novo variant c.902T > G, p.V301G; height at 14.6 yrs was 155cm (-2.7 SDS); no dysmorphic features; IGF1 deficiency (SDS −3.0)
Seq method: NGS short stature panel. Milder presentation delayed diagnosis and prevented treatment in these patients.

PMID: 31883394 Rughani et al., 2020
Young male Caucasian child with short stature, found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP; heterozygous for c.800G > A, p.Trp267* in GHR. At 23 months of age, his height was was 75.8 cm (−3.6 SDS). Method: GHR gene sequencing. Variant inherited from the patient's mother, whose height was 152 cm (−1.7 SDS).

PMID: 29188236 Vairamani et al., 2017
Report of three families with dominant-negative heterozygous mutations in the intracellular domain of GHR, causing a nonclassical GHI phenotype. Detected variants: c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C.
P1 - female with height 109.9 cm (−3.89 SD) at 8yrs 8 mo; low IGF1; variant inherited from a father with short stature (-2SD), strong family history of short stature (-2 to -4.4 SD) on father's side; WES
P2 - Spanish boy with height of 88.8 cm (−3.1 SD) at 3.8yrs; serum IGF-I was low normal; parents height: father -1.8SD and mother −2.46 SD) - variant inherited from the mother; targeted Sanger seq of GHR
P3 - 12yo female with short stature: 119.6 cm, −4.30 SD; high basal GH and low IGF-1 noted; father, mother, and grandfather all of very short stature (-3.6 to -4.3 SD). Variant in GHR inherited from the mother; targeted Sanger seq of GHR
P4 - Pakistani proband; height of 85.4 cm (−4.17 SD) at 4 yrs old; low IGF-I of 16 ng/mL (normal, 54 to 178); carried de novo GHR c.899dupC mutation and p.R229H missense variant inherited from the mother

PMID: 21900382 Derr et al., 2011 - FUNCTIONAL EVIDENCE for pathogenicity of GHR c.899dupC - mutant protein is expressed as normal, but found to be completely unresponsive to GH (no STAT5B phosphorylation); STAT5B activity was also significantly reduced when mutant protein was co-expressed with WT - confirmed dominant effect

GHR is associated with AR Laron dwarfism, OMIM:262500 and AD Growth hormone insensitivity, partial, OMIM:604271 in OMIM (accessed 8th June 2026).
Monogenic short stature v2.3 GHR Ida Ertmanska changed review comment from: RECESSIVE LARON DWARFISM:
PMID: 37474955 Bitarafan et al., 2023
Report of 3 sibs from a consanguineous Iranian family with Laron dwarfism. WES revealed the affected children were homozygous for GHR variant NM_000163.5; c.610 T>A, p.(Trp204Arg). Proband, 32yo male, had height of 146cm (-3.3 SDS) and skeletal maturity estimated at 13 years of age. Recurrent kidney stones also noted. Affected sibs' heights were -2.6 SDS and -4.6 SDS. 3 healthy brothers heterozygous for the variant had normal height; father's height was -2.1SDS, and mother's height -1.7SDS. Authors pose this variability comes from compensatory mechanisms.

PMID: 33912130 Li et al., 2021
4 male Chinese patients with proportionate short stature (height SDS of -5.49, -6.71, -3.95, and -2.80 at 3-14 yrs old). 3/4 patients had higher growth hormone (GH) levels than normal, and 3/4 cases had IGF-1 levels lower than the norm ( 4th case was borderline but very low). All 4 had bone age retardation (median 18 months delay), and there were no signs of pituitary abnormalities on MRI.
P3 had a heterozygous STOP-gain mutation (and most severe phenotype, height -6.71 SDS), P1 and P2 had biallelic missense mutations, and P4 harboured one missense and one frameshift variant, both inherited from unaffected parents. Caveat: only exons 2-10 of GHR were sequenced.

PMID: 34453441 Cottrell et al., 2021
2 kindreds of shared Italian ancestry (both from Campania). Homozygous deep intronic variant in GHR g.5:42700940T > G, c.618+836T>G results in loss of GHR function consistent with a severe GHI phenotype.

DOMINANT GH INSENSITIVITY:
PMID: 36943306 Andrews et al., 2023
Report of novel heterozygous GHR variants were identified in 2 unrelated patients with 'non-classical' GHI - posed to be dominant negative.
P1 - c.876-15T > G (rs199960137); height at 16.5 yrs was 153cm (−3.2 SDS); also presented with relative macrocephaly, disproportionate short stature borderline mesomelic shortening on skeletal survey
P2 - het de novo variant c.902T > G, p.V301G; height at 14.6 yrs was 155cm (-2.7 SDS); no dysmorphic features; IGF1 deficiency (SDS −3.0)
Seq method: NGS short stature panel. Milder presentation delayed diagnosis and prevented treatment in these patients.

PMID: 31883394 Rughani et al., 2020
Young male Caucasian child with short stature, found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP; heterozygous for c.800G > A, p.Trp267* in GHR. At 23 months of age, his height was was 75.8 cm (−3.6 SDS). Method: GHR gene sequencing. Variant inherited from the patient's mother, whose height was 152 cm (−1.7 SDS).

PMID: 29188236 Vairamani et al., 2017
Report of three families with dominant-negative heterozygous mutations in the intracellular domain of GHR, causing a nonclassical GHI phenotype. Detected variants: c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C.
P1 - height at 8yrs 8 mo was 109.9 cm (−3.89 SD); low IGF1; variant inherited from a father with short stature (-2SD), strong family history of short stature (-2 to -4.4 SD) on father's side
P2 -

GHR is associated with AR Laron dwarfism, OMIM:262500 and AD Growth hormone insensitivity, partial, OMIM:604271 in OMIM (accessed 8th June 2026).; to: RECESSIVE LARON DWARFISM:
PMID: 37474955 Bitarafan et al., 2023
Report of 3 sibs from a consanguineous Iranian family with Laron dwarfism. WES revealed the affected children were homozygous for GHR variant NM_000163.5; c.610 T>A, p.(Trp204Arg). Proband, 32yo male, had height of 146cm (-3.3 SDS) and skeletal maturity estimated at 13 years of age. Recurrent kidney stones also noted. Affected sibs' heights were -2.6 SDS and -4.6 SDS. 3 healthy brothers heterozygous for the variant had normal height; father's height was -2.1SDS, and mother's height -1.7SDS. Authors pose this variability comes from compensatory mechanisms.

PMID: 33912130 Li et al., 2021
4 male Chinese patients with proportionate short stature (height SDS of -5.49, -6.71, -3.95, and -2.80 at 3-14 yrs old). 3/4 patients had higher growth hormone (GH) levels than normal, and 3/4 cases had IGF-1 levels lower than the norm ( 4th case was borderline but very low). All 4 had bone age retardation (median 18 months delay), and there were no signs of pituitary abnormalities on MRI.
P3 had a heterozygous STOP-gain mutation (and most severe phenotype, height -6.71 SDS), P1 and P2 had biallelic missense mutations, and P4 harboured one missense and one frameshift variant, both inherited from unaffected parents. Caveat: only exons 2-10 of GHR were sequenced.

PMID: 34453441 Cottrell et al., 2021
2 kindreds of shared Italian ancestry (both from Campania). Homozygous deep intronic variant in GHR g.5:42700940T > G, c.618+836T>G results in loss of GHR function consistent with a severe GHI phenotype.

DOMINANT GH INSENSITIVITY:
PMID: 36943306 Andrews et al., 2023
Report of novel heterozygous GHR variants were identified in 2 unrelated patients with 'non-classical' GHI - posed to be dominant negative.
P1 - c.876-15T > G (rs199960137); height at 16.5 yrs was 153cm (−3.2 SDS); also presented with relative macrocephaly, disproportionate short stature borderline mesomelic shortening on skeletal survey
P2 - het de novo variant c.902T > G, p.V301G; height at 14.6 yrs was 155cm (-2.7 SDS); no dysmorphic features; IGF1 deficiency (SDS −3.0)
Seq method: NGS short stature panel. Milder presentation delayed diagnosis and prevented treatment in these patients.

PMID: 31883394 Rughani et al., 2020
Young male Caucasian child with short stature, found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP; heterozygous for c.800G > A, p.Trp267* in GHR. At 23 months of age, his height was was 75.8 cm (−3.6 SDS). Method: GHR gene sequencing. Variant inherited from the patient's mother, whose height was 152 cm (−1.7 SDS).

PMID: 29188236 Vairamani et al., 2017
Report of three families with dominant-negative heterozygous mutations in the intracellular domain of GHR, causing a nonclassical GHI phenotype. Detected variants: c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C.
P1 - female with height 109.9 cm (−3.89 SD) at 8yrs 8 mo; low IGF1; variant inherited from a father with short stature (-2SD), strong family history of short stature (-2 to -4.4 SD) on father's side; WES
P2 - Spanish boy with height of 88.8 cm (−3.1 SD) at 3.8yrs; serum IGF-I was low normal; parents height: father -1.8SD and mother −2.46 SD) - variant inherited from the mother; targeted Sanger seq of GHR
P3 - 12yo female with short stature: 119.6 cm, −4.30 SD; high basal GH and low IGF-1 noted; father, mother, and grandfather all of very short stature (-3.6 to -4.3 SD). Variant in GHR inherited from the mother; targeted Sanger seq of GHR
P4 - Pakistani proband; height of 85.4 cm (−4.17 SD) at 4 yrs old; low IGF-I of 16 ng/mL (normal, 54 to 178); carried de novo GHR c.899dupC mutation and p.R229H missense variant inherited from the mother

GHR is associated with AR Laron dwarfism, OMIM:262500 and AD Growth hormone insensitivity, partial, OMIM:604271 in OMIM (accessed 8th June 2026).
Monogenic short stature v2.3 GHR Ida Ertmanska edited their review of gene: GHR: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Monogenic short stature v2.3 GHR Ida Ertmanska changed review comment from: RECESSIVE LARON DWARFISM:
PMID: 37474955 Bitarafan et al., 2023
Report of 3 sibs from a consanguineous Iranian family with Laron dwarfism. WES revealed the affected children were homozygous for GHR variant NM_000163.5; c.610 T>A, p.(Trp204Arg). Proband, 32yo male, had height of 146cm (-3.3 SDS) and skeletal maturity estimated at 13 years of age. Recurrent kidney stones also noted. Affected sibs' heights were -2.6 SDS and -4.6 SDS. 3 healthy brothers heterozygous for the variant had normal height; father's height was -2.1SDS, and mother's height -1.7SDS. Authors pose this variability comes from compensatory mechanisms.

PMID: 33912130 Li et al., 2021
4 male Chinese patients with proportionate short stature (height SDS of -5.49, -6.71, -3.95, and -2.80 at 3-14 yrs old). 3/4 patients had higher growth hormone (GH) levels than normal, and 3/4 cases had IGF-1 levels lower than the norm ( 4th case was borderline but very low). All 4 had bone age retardation (median 18 months delay), and there were no signs of pituitary abnormalities on MRI.
P3 had a heterozygous STOP-gain mutation (and most severe phenotype, height -6.71 SDS), P1 and P2 had biallelic missense mutations, and P4 harboured one missense and one frameshift variant, both inherited from unaffected parents. Caveat: only exons 2-10 of GHR were sequenced.

PMID: 34453441 Cottrell et al., 2021
2 kindreds of shared Italian ancestry (both from Campania). Homozygous deep intronic variant in GHR g.5:42700940T > G, c.618+836T>G results in loss of GHR function consistent with a severe GHI phenotype.

DOMINANT GH INSENSITIVITY:
PMID: 36943306 Andrews et al., 2023
Report of novel heterozygous GHR variants were identified in 2 unrelated patients with 'non-classical' GHI - posed to be dominant negative.
P1 - c.876-15T > G (rs199960137); height at 16.5 yrs was 153cm (−3.2 SDS); also presented with relative macrocephaly, disproportionate short stature borderline mesomelic shortening on skeletal survey
P2 - het de novo variant c.902T > G, p.V301G; height at 14.6 yrs was 155cm (-2.7 SDS); no dysmorphic features; IGF1 deficiency (SDS −3.0)
Seq method: NGS short stature panel. Milder presentation delayed diagnosis and prevented treatment in these patients.

GHR is associated with AR Laron dwarfism, OMIM:262500 and AD Growth hormone insensitivity, partial, OMIM:604271 in OMIM (accessed 8th June 2026).; to: RECESSIVE LARON DWARFISM:
PMID: 37474955 Bitarafan et al., 2023
Report of 3 sibs from a consanguineous Iranian family with Laron dwarfism. WES revealed the affected children were homozygous for GHR variant NM_000163.5; c.610 T>A, p.(Trp204Arg). Proband, 32yo male, had height of 146cm (-3.3 SDS) and skeletal maturity estimated at 13 years of age. Recurrent kidney stones also noted. Affected sibs' heights were -2.6 SDS and -4.6 SDS. 3 healthy brothers heterozygous for the variant had normal height; father's height was -2.1SDS, and mother's height -1.7SDS. Authors pose this variability comes from compensatory mechanisms.

PMID: 33912130 Li et al., 2021
4 male Chinese patients with proportionate short stature (height SDS of -5.49, -6.71, -3.95, and -2.80 at 3-14 yrs old). 3/4 patients had higher growth hormone (GH) levels than normal, and 3/4 cases had IGF-1 levels lower than the norm ( 4th case was borderline but very low). All 4 had bone age retardation (median 18 months delay), and there were no signs of pituitary abnormalities on MRI.
P3 had a heterozygous STOP-gain mutation (and most severe phenotype, height -6.71 SDS), P1 and P2 had biallelic missense mutations, and P4 harboured one missense and one frameshift variant, both inherited from unaffected parents. Caveat: only exons 2-10 of GHR were sequenced.

PMID: 34453441 Cottrell et al., 2021
2 kindreds of shared Italian ancestry (both from Campania). Homozygous deep intronic variant in GHR g.5:42700940T > G, c.618+836T>G results in loss of GHR function consistent with a severe GHI phenotype.

DOMINANT GH INSENSITIVITY:
PMID: 36943306 Andrews et al., 2023
Report of novel heterozygous GHR variants were identified in 2 unrelated patients with 'non-classical' GHI - posed to be dominant negative.
P1 - c.876-15T > G (rs199960137); height at 16.5 yrs was 153cm (−3.2 SDS); also presented with relative macrocephaly, disproportionate short stature borderline mesomelic shortening on skeletal survey
P2 - het de novo variant c.902T > G, p.V301G; height at 14.6 yrs was 155cm (-2.7 SDS); no dysmorphic features; IGF1 deficiency (SDS −3.0)
Seq method: NGS short stature panel. Milder presentation delayed diagnosis and prevented treatment in these patients.

PMID: 31883394 Rughani et al., 2020
Young male Caucasian child with short stature, found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP; heterozygous for c.800G > A, p.Trp267* in GHR. At 23 months of age, his height was was 75.8 cm (−3.6 SDS). Method: GHR gene sequencing. Variant inherited from the patient's mother, whose height was 152 cm (−1.7 SDS).

PMID: 29188236 Vairamani et al., 2017
Report of three families with dominant-negative heterozygous mutations in the intracellular domain of GHR, causing a nonclassical GHI phenotype. Detected variants: c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C.
P1 - height at 8yrs 8 mo was 109.9 cm (−3.89 SD); low IGF1; variant inherited from a father with short stature (-2SD), strong family history of short stature (-2 to -4.4 SD) on father's side
P2 -

GHR is associated with AR Laron dwarfism, OMIM:262500 and AD Growth hormone insensitivity, partial, OMIM:604271 in OMIM (accessed 8th June 2026).
Monogenic short stature v2.3 GHR Ida Ertmanska edited their review of gene: GHR: Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic short stature v2.3 GHR Ida Ertmanska reviewed gene: GHR: Rating: ; Mode of pathogenicity: None; Publications: 33912130, 34453441, 36943306, 37474955; Phenotypes: Laron dwarfism, OMIM:262500, Growth hormone insensitivity, partial, OMIM:604271; Mode of inheritance: None
Congenital myopathy v7.46 P4HA1 Ida Ertmanska Classified gene: P4HA1 as Red List (low evidence)
Congenital myopathy v7.46 P4HA1 Ida Ertmanska Added comment: Comment on list classification: There is only 1 pedigree reported in literature where individuals harboured biallelic P4HA1 variants and presented with a connective tissue disorder. The symptoms had some overlap with EDS, including joint hypermobility, congenital hypotonia / muscle weakness, and contractures, but no evidence of vascular rupture or kyphoscoliosis. P4ha1 null mice are embryonic lethal. Based on available evidence, this gene should be rated Red, until more evidence emerges.
Congenital myopathy v7.46 P4HA1 Ida Ertmanska Gene: p4ha1 has been classified as Red List (Low Evidence).
Arthrogryposis v10.9 P4HA1 Ida Ertmanska Classified gene: P4HA1 as Red List (low evidence)
Arthrogryposis v10.9 P4HA1 Ida Ertmanska Added comment: Comment on list classification: There is only 1 pedigree reported in literature where individuals harboured biallelic P4HA1 variants and presented with a connective tissue disorder. The symptoms had some overlap with EDS, including joint hypermobility, congenital hypotonia / muscle weakness, and contractures, but no evidence of vascular rupture or kyphoscoliosis. P4ha1 null mice are embryonic lethal. Based on available evidence, this gene should be rated Red, until more evidence emerges.
Arthrogryposis v10.9 P4HA1 Ida Ertmanska Gene: p4ha1 has been classified as Red List (Low Evidence).
Ehlers Danlos syndrome with a likely monogenic cause v4.13 P4HA1 Ida Ertmanska Classified gene: P4HA1 as Red List (low evidence)
Ehlers Danlos syndrome with a likely monogenic cause v4.13 P4HA1 Ida Ertmanska Added comment: Comment on list classification: There is only 1 pedigree reported in literature where individuals harboured biallelic P4HA1 variants and presented with a connective tissue disorder. The symptoms had some overlap with EDS, including joint hypermobility, congenital hypotonia / muscle weakness, and contractures, but no evidence of vascular rupture or kyphoscoliosis. P4ha1 null mice are embryonic lethal. Based on available evidence, this gene should be rated Red, until more evidence emerges.
Ehlers Danlos syndrome with a likely monogenic cause v4.13 P4HA1 Ida Ertmanska Gene: p4ha1 has been classified as Red List (Low Evidence).
Congenital myopathy v7.45 P4HA1 Ida Ertmanska gene: P4HA1 was added
gene: P4HA1 was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: P4HA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P4HA1 were set to 17135260; 28419360
Phenotypes for gene: P4HA1 were set to connective tissue disorder, MONDO:0003900
Review for gene: P4HA1 was set to RED
Added comment: PMID: 28419360 Zou et al., 2017
Report of 2 sibs with early-onset joint hypermobility, joint contractures, muscle weakness, mild bone dysplasia, as well as high myopia. Biallelic P4HA1 mutations detected: c.1543 + 2 T > G (predicted to cause exon 12 skipping: p.Ala418_Arg434del) and c.1323_1324insAG, p.Arg362Glyfs*9. Seq method: WES. Variants confirmed in trans.
Muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane.

PMID: 17135260 Holster et al., 2007
P4ha1-/- null mice are embryonically lethal with evidence of impaired assembly of collagen IV at the basement membrane, whereas P4ha1+/- mice have no abnormalities
Sources: Literature
Arthrogryposis v10.8 P4HA1 Ida Ertmanska gene: P4HA1 was added
gene: P4HA1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: P4HA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P4HA1 were set to 17135260; 28419360
Phenotypes for gene: P4HA1 were set to connective tissue disorder, MONDO:0003900
Review for gene: P4HA1 was set to RED
Added comment: PMID: 28419360 Zou et al., 2017
Report of 2 sibs with early-onset joint hypermobility, joint contractures, muscle weakness, mild bone dysplasia, as well as high myopia. Biallelic P4HA1 mutations detected: c.1543 + 2 T > G (predicted to cause exon 12 skipping: p.Ala418_Arg434del) and c.1323_1324insAG, p.Arg362Glyfs*9. Seq method: WES. Variants confirmed in trans.
Muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane.

PMID: 17135260 Holster et al., 2007
P4ha1-/- null mice are embryonically lethal with evidence of impaired assembly of collagen IV at the basement membrane, whereas P4ha1+/- mice have no abnormalities
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v4.12 P4HA1 Ida Ertmanska gene: P4HA1 was added
gene: P4HA1 was added to Ehlers Danlos syndrome with a likely monogenic cause. Sources: Literature
Mode of inheritance for gene: P4HA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P4HA1 were set to 17135260; 28419360
Phenotypes for gene: P4HA1 were set to connective tissue disorder, MONDO:0003900
Review for gene: P4HA1 was set to RED
Added comment: PMID: 28419360 Zou et al., 2017
Report of 2 sibs with early-onset joint hypermobility, joint contractures, muscle weakness, mild bone dysplasia, as well as high myopia. Biallelic P4HA1 mutations detected: c.1543 + 2 T > G (predicted to cause exon 12 skipping: p.Ala418_Arg434del) and c.1323_1324insAG, p.Arg362Glyfs*9. Seq method: WES. Variants confirmed in trans.
Muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane.

PMID: 17135260 Holster et al., 2007
P4ha1-/- null mice are embryonically lethal with evidence of impaired assembly of collagen IV at the basement membrane, whereas P4ha1+/- mice have no abnormalities
Sources: Literature
Amelogenesis imperfecta v4.36 CLDN19 Ida Ertmanska changed review comment from: Comment on list classification: As there are more than 3 unrelated individuals reported in literature with biallelic CLDN19 variants and amelogenesis imperfecta, this gene can be promoted to Green at the next update.; to: Comment on list classification: As there are more than 3 unrelated individuals reported in literature with biallelic CLDN19 variants and amelogenesis imperfecta, this gene can be promoted to Green at the next update. However, since the families come from one study, and no other cases have been reported to date, this gene is tagged for expert review regarding strength of evidence.
Amelogenesis imperfecta v4.36 CLDN19 Ida Ertmanska changed review comment from: As reviewed previously by Sarah and Rebecca, there are 6 unrelated families reported in PMID: 27530400 from 2 different ethnic backgrounds. 4 different variants were detected: p.Arg200Gln, p.Gly20Asp, and p.Leu90Arg, p.Gln57*, and p.Gly20Asp (either comp het or homozygous in each proband).

CLDN19:c.599G>A, p.Arg200Gln has MAF = 0.03402 in gnomAD v4.1.1. It is also categorically classified as Benign in ClinVar.
CLDN19:c.59G>A, p.Gly20Asp has MAF = 0.0003840 in gnomAD v4.1. (no homozygotes). Revel score = 0.89 (Moderate).
CLDN19:c.269T>G, p.Leu90Arg is not found in gnomAD v4.1.1. Revel score = 0.96 (Strong).
CLDN19:c.169C>T, p.Gln57* - not in gnomAD v4.1.1.
Thus, 3/4 variants are plausibly P/LP - 5/6 families can be included in the scoring.

CLDN19 is associated with AR Hypomagnesemia 5, renal, with ocular involvement, OMIM:248190 in OMIM (Accessed 5th June 2026). This gene is also Green on the Amelogenesis imperfecta panel in PanelApp Australia.; to: As reviewed previously by Sarah and Rebecca, there are 6 unrelated families reported in PMID: 27530400 from 2 different ethnic backgrounds. 4 different variants were detected: p.Arg200Gln, p.Gly20Asp, and p.Leu90Arg, p.Gln57*, and p.Gly20Asp (either comp het or homozygous in each proband).

CLDN19:c.599G>A, p.Arg200Gln has MAF = 0.03402 in gnomAD v4.1.1. It is also categorically classified as Benign in ClinVar.
CLDN19:c.59G>A, p.Gly20Asp has MAF = 0.0003840 in gnomAD v4.1. (no homozygotes). Revel score = 0.89 (Moderate).
CLDN19:c.269T>G, p.Leu90Arg is not found in gnomAD v4.1.1. Revel score = 0.96 (Strong).
CLDN19:c.169C>T, p.Gln57* - not in gnomAD v4.1.1.
Thus, 3/4 variants are plausibly P/LP - 5/6 families can be included in the scoring.

CLDN19 is associated with AR Hypomagnesemia 5, renal, with ocular involvement, OMIM:248190 in OMIM (Accessed 5th June 2026). This gene is also Green on the Amelogenesis imperfecta panel in PanelApp Australia.
Amelogenesis imperfecta v4.36 CLDN19 Ida Ertmanska Tag Q2_26_expert_review tag was added to gene: CLDN19.
Amelogenesis imperfecta v4.36 CLDN19 Ida Ertmanska Phenotypes for gene: CLDN19 were changed from Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis (FHHNC) to Hypomagnesemia 5, renal, with ocular involvement, OMIM:248190
Amelogenesis imperfecta v4.35 CLDN19 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CLDN19.
Amelogenesis imperfecta v4.35 CLDN19 Ida Ertmanska commented on gene: CLDN19: Comment on list classification: As there are more than 3 unrelated individuals reported in literature with biallelic CLDN19 variants and amelogenesis imperfecta, this gene can be promoted to Green at the next update.
Amelogenesis imperfecta v4.35 CLDN19 Ida Ertmanska changed review comment from: As reviewed previously by Sarah and Rebecca, there are 6 unrelated families reported in PMID: 27530400 from 2 different ethnic backgrounds. 4 different variants were detected: p.Arg200Gln, p.Gly20Asp, and p.Leu90Arg, p.Gln57*, and p.Gly20Asp (either comp het or homozygous in each proband).

CLDN19:c.599G>A, p.Arg200Gln has MAF = 0.03402 in gnomAD v4.1.1. It is also categorically classified as Benign in ClinVar.
CLDN19:c.59G>A, p.Gly20Asp has MAF = 0.0003840 in gnomAD v4.1. (no homozygotes). Revel score = 0.89 (Moderate).
CLDN19:c.269T>G, p.Leu90Arg is not found in gnomAD v4.1.1. Revel score = 0.96 (Strong).
CLDN19:c.169C>T, p.Gln57* - not in gnomAD v4.1.1.
Thus, 3/4 variants are plausibly P/LP - 5/6 families can be included in the scoring.

CLDN19 is associated with AR Hypomagnesemia 5, renal, with ocular involvement, OMIM:248190 in OMIM (Accessed 5th June 2026).; to: As reviewed previously by Sarah and Rebecca, there are 6 unrelated families reported in PMID: 27530400 from 2 different ethnic backgrounds. 4 different variants were detected: p.Arg200Gln, p.Gly20Asp, and p.Leu90Arg, p.Gln57*, and p.Gly20Asp (either comp het or homozygous in each proband).

CLDN19:c.599G>A, p.Arg200Gln has MAF = 0.03402 in gnomAD v4.1.1. It is also categorically classified as Benign in ClinVar.
CLDN19:c.59G>A, p.Gly20Asp has MAF = 0.0003840 in gnomAD v4.1. (no homozygotes). Revel score = 0.89 (Moderate).
CLDN19:c.269T>G, p.Leu90Arg is not found in gnomAD v4.1.1. Revel score = 0.96 (Strong).
CLDN19:c.169C>T, p.Gln57* - not in gnomAD v4.1.1.
Thus, 3/4 variants are plausibly P/LP - 5/6 families can be included in the scoring.

CLDN19 is associated with AR Hypomagnesemia 5, renal, with ocular involvement, OMIM:248190 in OMIM (Accessed 5th June 2026). This gene is also Green on the Amelogenesis imperfecta panel in PanelApp Australia.
Amelogenesis imperfecta v4.35 CLDN19 Ida Ertmanska reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: None; Publications: 27530400; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, OMIM:248190; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.35 SMOC2 Ida Ertmanska changed review comment from: 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.
Sources: Literature; to: 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
Amelogenesis imperfecta v4.35 SMOC2 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: SMOC2.
Amelogenesis imperfecta v4.35 SMOC2 Ida Ertmanska Classified gene: SMOC2 as Amber List (moderate evidence)
Amelogenesis imperfecta v4.35 SMOC2 Ida Ertmanska Gene: smoc2 has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.34 SMOC2 Ida Ertmanska gene: SMOC2 was added
gene: SMOC2 was added to Amelogenesis imperfecta. Sources: Literature
Q2_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.
Sources: Literature
Likely inborn error of metabolism v9.7 CLCN7 Ida Ertmanska Phenotypes for gene: CLCN7 were changed from Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541 to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541; hypopigmentation, organomegaly, and delayed myelination and development, MONDO:0032805
Albinism or congenital nystagmus v4.11 CLCN7 Ida Ertmanska Phenotypes for gene: CLCN7 were changed from Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541 to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541; hypopigmentation, organomegaly, and delayed myelination and development, MONDO:0032805
Albinism or congenital nystagmus v4.10 CLCN7 Ida Ertmanska Publications for gene: CLCN7 were set to 31155284
Albinism or congenital nystagmus v4.9 CLCN7 Ida Ertmanska Mode of inheritance for gene: CLCN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Albinism or congenital nystagmus v4.8 CLCN7 Ida Ertmanska Tag watchlist was removed from gene: CLCN7.
Tag Q2_26_promote_green tag was added to gene: CLCN7.
Albinism or congenital nystagmus v4.8 CLCN7 Ida Ertmanska commented on gene: CLCN7: Comment on list classification: There are now 5 unrelated individuals (4 male, 1 female) with Hypopigmentation, organomegaly, and delayed myelination and development, harbouring heterozygous CLCN7 variants. 4/5 patients had confirmed de novo status. 2 different variants were reported, with p.Tyr715Cys recurring in 4 unrelated patients. Based on available evidence, CLCN7 should be promoted to Green on Albinism or congenital nystagmus.
Albinism or congenital nystagmus v4.8 CLCN7 Ida Ertmanska reviewed gene: CLCN7: Rating: GREEN; Mode of pathogenicity: None; Publications: 38838776, 39056574; Phenotypes: Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v9.6 CLCN7 Ida Ertmanska changed review comment from: PMID: 38838776 Polovitskaya et al., 2024
Report of unrelated male 2 individuals with hypopigmentation, muscular hypotonia, failure to thrive, organomegaly, delayed myelination, and psychomotor developmental disorder (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys (inheritance not confirmed) and p.Lys285Thr (de novo).

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with significant developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.; to: PMID: 38838776 Polovitskaya et al., 2024
Report of unrelated male 2 individuals with hypopigmentation, muscular hypotonia, failure to thrive, organomegaly, delayed myelination, and psychomotor developmental disorder (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys (inheritance not confirmed) and p.Lys285Thr (de novo).
Patient fibroblast studies showed that both disease-associated mutations affect the inhibition of ClC-7 by PI(3,5)P2 and shift its voltage-dependent gating to more physiological lysosomal voltages.

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with significant developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.
Lysosomal storage disorder v3.9 CLCN7 Ida Ertmanska changed review comment from: PMID: 38838776 Polovitskaya et al., 2024
Report of unrelated male 2 individuals with hypopigmentation, muscular hypotonia, failure to thrive, organomegaly, delayed myelination, and psychomotor developmental disorder (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys (inheritance not confirmed) and p.Lys285Thr (de novo).

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with significant developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.; to: PMID: 38838776 Polovitskaya et al., 2024
Report of unrelated male 2 individuals with hypopigmentation, muscular hypotonia, failure to thrive, organomegaly, delayed myelination, and psychomotor developmental disorder (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys (inheritance not confirmed) and p.Lys285Thr (de novo).
Patient fibroblast studies showed that both disease-associated mutations affect the inhibition of ClC-7 by PI(3,5)P2 and shift its voltage-dependent gating to more physiological lysosomal voltages.

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with significant developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.
Likely inborn error of metabolism v9.6 CLCN7 Ida Ertmanska commented on gene: CLCN7: Comment on list classification: There are now 5 unrelated individuals (4 male, 1 female) with Hypopigmentation, organomegaly, and delayed myelination and development, harbouring heterozygous CLCN7 variants. 4/5 patients had confirmed de novo status. 2 different variants were reported, with p.Tyr715Cys recurring in 4 unrelated patients. Based on available evidence, CLCN7 should be promoted to Green on Likely inborn error of metabolism.
Lysosomal storage disorder v3.9 CLCN7 Ida Ertmanska commented on gene: CLCN7: Comment on list classification: There are now 5 unrelated individuals (4 male, 1 female) with Hypopigmentation, organomegaly, and delayed myelination and development, harbouring heterozygous CLCN7 variants. 4/5 patients had confirmed de novo status. 2 different variants were reported, with p.Tyr715Cys recurring in 4 unrelated patients. Based on available evidence, CLCN7 should be promoted to Green on Lysosomal storage disorder.
Likely inborn error of metabolism v9.6 CLCN7 Ida Ertmanska Publications for gene: CLCN7 were set to 31155284
Likely inborn error of metabolism v9.5 CLCN7 Ida Ertmanska Mode of inheritance for gene: CLCN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v9.4 CLCN7 Ida Ertmanska Tag watchlist was removed from gene: CLCN7.
Tag Q2_26_promote_green tag was added to gene: CLCN7.
Lysosomal storage disorder v3.9 CLCN7 Ida Ertmanska changed review comment from: PMID: 38838776 Polovitskaya et al., 2024
Report of 2 individuals with hypopigmentation, organomegaly, and delayed myelination and development (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys and novel p.Lys285Thr.

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.; to: PMID: 38838776 Polovitskaya et al., 2024
Report of unrelated male 2 individuals with hypopigmentation, muscular hypotonia, failure to thrive, organomegaly, delayed myelination, and psychomotor developmental disorder (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys (inheritance not confirmed) and p.Lys285Thr (de novo).

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with significant developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.
Likely inborn error of metabolism v9.4 CLCN7 Ida Ertmanska changed review comment from: PMID: 38838776 Polovitskaya et al., 2024
Report of 2 individuals with hypopigmentation, organomegaly, and delayed myelination and development (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys and novel p.Lys285Thr.

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.; to: PMID: 38838776 Polovitskaya et al., 2024
Report of unrelated male 2 individuals with hypopigmentation, muscular hypotonia, failure to thrive, organomegaly, delayed myelination, and psychomotor developmental disorder (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys (inheritance not confirmed) and p.Lys285Thr (de novo).

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with significant developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.
Likely inborn error of metabolism v9.4 CLCN7 Ida Ertmanska changed review comment from: PMID: 38838776 Polovitskaya et al., 2024
Report of 2 individuals with hypopigmentation, organomegaly, and delayed myelination and development (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys and novel p.Lys285Thr.

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.; to: PMID: 38838776 Polovitskaya et al., 2024
Report of 2 individuals with hypopigmentation, organomegaly, and delayed myelination and development (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys and novel p.Lys285Thr.

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.
Likely inborn error of metabolism v9.4 CLCN7 Ida Ertmanska reviewed gene: CLCN7: 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: 38838776, 39056574; Phenotypes: Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Lysosomal storage disorder v3.9 CLCN7 Ida Ertmanska Phenotypes for gene: CLCN7 were changed from Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541 to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541; hypopigmentation, organomegaly, and delayed myelination and development, MONDO:0032805
Lysosomal storage disorder v3.8 CLCN7 Ida Ertmanska Publications for gene: CLCN7 were set to 31155284
Lysosomal storage disorder v3.7 CLCN7 Ida Ertmanska Mode of inheritance for gene: CLCN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Lysosomal storage disorder v3.6 CLCN7 Ida Ertmanska Tag watchlist was removed from gene: CLCN7.
Tag Q2_26_promote_green tag was added to gene: CLCN7.
Lysosomal storage disorder v3.6 CLCN7 Ida Ertmanska reviewed gene: CLCN7: Rating: GREEN; Mode of pathogenicity: None; Publications: 38838776, 39056574; Phenotypes: Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v8.9 NPR2 Ida Ertmanska changed review comment from: Comment on list classification: There are 27 individuals reported in PMID: 40424589 with heterozygous NPR2 variants and idiopathic short stature, with limb disorders being the main skeletal feature. Brachydactyly was present in 13/27 individuals. Clinodactyly and syndactyly have also been reported. Hence, the rating should be promoted to Green on Limb disorders at the next GMS update.; to: Comment on list classification: There are 27 individuals reported in PMID: 40424589 with heterozygous NPR2 variants and idiopathic short stature, with limb disorders being the main skeletal feature. Brachydactyly was present in 13/27 individuals. Clinodactyly and syndactyly have also been reported. Brachydactyly is also a consistent feature in recessive NPR2-related skeletal dysplasia (Acromesomelic dysplasia 1, Maroteaux type). Hence, the rating should be promoted to Green on Limb disorders at the next GMS update, with MOI set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Limb disorders v8.9 NPR2 Ida Ertmanska Classified gene: NPR2 as Amber List (moderate evidence)
Limb disorders v8.9 NPR2 Ida Ertmanska Added comment: Comment on list classification: There are 27 individuals reported in PMID: 40424589 with heterozygous NPR2 variants and idiopathic short stature, with limb disorders being the main skeletal feature. Brachydactyly was present in 13/27 individuals. Clinodactyly and syndactyly have also been reported. Hence, the rating should be promoted to Green on Limb disorders at the next GMS update.
Limb disorders v8.9 NPR2 Ida Ertmanska Gene: npr2 has been classified as Amber List (Moderate Evidence).
Limb disorders v8.8 NPR2 Ida Ertmanska edited their review of gene: NPR2: Changed rating: GREEN; Changed publications to: 40424589; Changed phenotypes to: Short stature with nonspecific skeletal abnormalities, OMIM:616255; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb disorders v8.8 NPR2 Ida Ertmanska commented on gene: NPR2
Limb disorders v8.8 NPR2 Ida Ertmanska Deleted their review
Limb disorders v8.8 NPR2 Ida Ertmanska gene: NPR2 was added
gene: NPR2 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: NPR2.
Mode of inheritance for gene: NPR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NPR2 were set to 40424589
Phenotypes for gene: NPR2 were set to Short stature with nonspecific skeletal abnormalities, OMIM:616255
Review for gene: NPR2 was set to GREEN
Added comment: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 had brachydactyly; clinodactyly and syndactyly were also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).
Sources: Literature
Limb disorders v8.8 NPR2 Ida Ertmanska gene: NPR2 was added
gene: NPR2 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: NPR2.
Mode of inheritance for gene: NPR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NPR2 were set to 40424589
Phenotypes for gene: NPR2 were set to Short stature with nonspecific skeletal abnormalities, OMIM:616255
Review for gene: NPR2 was set to GREEN
Added comment: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 had brachydactyly; clinodactyly and syndactyly were also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).
Sources: Literature
Limb disorders v8.8 NPR2 Ida Ertmanska gene: NPR2 was added
gene: NPR2 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: NPR2.
Mode of inheritance for gene: NPR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NPR2 were set to 40424589
Phenotypes for gene: NPR2 were set to Short stature with nonspecific skeletal abnormalities, OMIM:616255
Review for gene: NPR2 was set to GREEN
gene: NPR2 was marked as current diagnostic
Added comment: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 had brachydactyly; clinodactyly and syndactyly were also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement).
Sources: Literature
Fetal anomalies v7.11 NPR2 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: NPR2.
Fetal anomalies v7.11 NPR2 Ida Ertmanska edited their review of gene: NPR2: Changed rating: GREEN; Changed publications to: 40424589; Changed phenotypes to: Short stature with nonspecific skeletal abnormalities, OMIM:616255; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v7.11 NPR2 Ida Ertmanska changed review comment from: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals (> 2 years old and height <-3SD).; to: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia: mild dysproportion, cone-shaped epiphysis, and shortened metacarpals. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals (> 2 years old and height <-3SD).

Consider MOI change to BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as heterozygous individuals also present with skeletal features, limb disorders.
Fetal anomalies v7.11 NPR2 Ida Ertmanska commented on gene: NPR2
Monogenic short stature v2.3 NPR2 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: NPR2.
Monogenic short stature v2.3 NPR2 Ida Ertmanska Publications for gene: NPR2 were set to
Monogenic short stature v2.2 NPR2 Ida Ertmanska Phenotypes for gene: NPR2 were changed from Acromesomelic dysplasia 1, Maroteaux type, OMIM:602875 to Acromesomelic dysplasia 1, Maroteaux type, OMIM:602875; Short stature with nonspecific skeletal abnormalities, OMIM:616255
Monogenic short stature v2.1 NPR2 Ida Ertmanska commented on gene: NPR2: Comment on mode of inheritance: There are more than 3 unrelated individuals reported in literature with heterozygous NPR2 variants and idiopathic short stature, more severe than -3SD at age >2yrs. Biallelic variants are known to cause severe dwarfism, with stature well below -3SD. Hence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Monogenic short stature v2.1 NPR2 Ida Ertmanska changed review comment from: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals.; to: PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals (> 2 years old and height <-3SD).
Monogenic short stature v2.1 NPR2 Ida Ertmanska edited their review of gene: NPR2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic short stature v2.1 NPR2 Ida Ertmanska edited their review of gene: NPR2: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic short stature v2.1 NPR2 Ida Ertmanska reviewed gene: NPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40424589; Phenotypes: Short stature with nonspecific skeletal abnormalities, OMIM:616255; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: Following on the review from Terri McVeigh, request for demotion of this gene from green rating has been requested by the NHS Genomic Medicine Service and verbally agreed with PanelApp team.

This change was requested because there are no clinical guidelines to manage variants on this gene on this panel.

This change will be implemented at the next update - tagging for demotion.; to: Comment on list classification: Following on the review from Terri McVeigh, request for demotion of this gene from green rating has been requested by the NHS Genomic Medicine Service and verbally agreed with PanelApp team.

This change was requested due to all the reasons described in Terri McVeigh's review.

This change will be implemented at the next update - tagging for demotion.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.13 CFI Ida Ertmanska edited their review of gene: CFI: Changed publications to: 26895476, 26283675, 31919107, 37615951
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.13 CFI Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants".

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants".

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFI and AD C3 glomerulonephriti has been classified as Moderate in ClinGen (June 2024); association with AD atypical hemolytic-uremic syndrome was ranked as Definitive (June 2023).
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.13 CFI Ida Ertmanska Phenotypes for gene: CFI were changed from C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Immune-complex-mediated MPGN; Hemolytic uremic syndrome, atypical, susceptibility to, 3,612923 to {Hemolytic uremic syndrome, atypical, susceptibility to, 3}, OMIM:612923; Complement factor I deficiency, OMIM:610984; C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.12 CFI Ida Ertmanska Publications for gene: CFI were set to 24172683; 18371543; 22456601; 27458560
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska Deleted their comment
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants".

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation. Of note, 90% of CFI variants identified in patients have been reported in gnomAD (most CFH variants are absent), suggesting that genetic susceptibility induced by CFI variants may be lower than those of CFH variants.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska changed review comment from: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported 16 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 13 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.; to: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported 16 individuals with rare CFI variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 13 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska commented on gene: CFI: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported 16 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 13 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFH Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report. Authors found that CFH variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFH Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report. Authors found that CFH variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed. Authors found that CFI variants are associated with more severe C3G, and early, frequent recurrence after kidney transplantation.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (17 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (16 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels. 12/16 patients had confirmed C3 glomerulopathy and 4 had Ig-MPGN confirmed by histologic data. Kidney failure (dialysis or transplantation) was confirmed in 13/16 patients assessed.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (13 variants, 24%), C3, and CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI (17 patients, 13 variants, 24%), C3, and CFH. Thrombotic microangiopathy was present in 5/14 cases with CFI variants. 11 (84%) Pathogenic variants with decreased factor I production. Presence of a rare variant was associated with poor kidney survival. 5 variants yielded normal FI plasma levels, and 8 resulted in low FI plasma levels.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFI Ida Ertmanska reviewed gene: CFI: Rating: GREEN; Mode of pathogenicity: None; Publications: 31919107, 37615951; Phenotypes: {Hemolytic uremic syndrome, atypical, susceptibility to, 3}, OMIM:612923, Complement factor I deficiency, OMIM:610984; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.11 CFH Ida Ertmanska Phenotypes for gene: CFH were changed from C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Hemolytic uremic syndrome, atypical, susceptibility to, 1, 235400; Dense Deposit Disease; Membranoproliferative Glomerulonephritis Type II; Immune-complex-mediated MPGN to Complement factor H deficiency, OMIM:609814; {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.10 CFH Ida Ertmanska Publications for gene: CFH were set to 24172683; 16612335; 24722444; 27458560; 9312129
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska Tag Q2_26_MOI tag was added to gene: CFH.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska edited their review of gene: CFH: Changed publications to: 26895476, 26283675, 31919107, 37615951
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.
Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.

Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

CFH genetic abnormalities were reported at 3.7% and 16% in the Italian and US cohorts (PMID: 26895476 & PMID: 26283675). In the US cohort, C3 patient cohort was enriched for rare variants in CFH, CFI, CFHR5, and CD46 genes (P<0.05). Italian study poses that "presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants" e.g. CFH V62.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.
Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than complement dysregulation driving disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.
Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than genetic complement dysregulation driving the disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.
Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than complement dysregulation driving disease.

PMID: 34211499 Piras et al., 2021
Authors state approx 20% of cases are familial. MLPA study of patients with C3G (n = 103) and IC-MPGN (n = 96). Detected a deletion of the entire CFH, CFHR3, and CFHR1 in one patient with IC-MPGN, as well as CNVs in other CFH-related genes.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.
Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than complement dysregulation driving disease.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska edited their review of gene: CFH: Changed publications to: 37615951, 31919107
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.
Authors acknowledge the Levine et al., 2020 study that found no enrichment, but dispute the methodology: "In this large series, 45% of patients with Ig-MPGN had a low C4 level, suggesting that secondary forms with the activation of the classical pathway may have been included in the study." - low C4 points to secondary MPGN, rather than complement dysregulation driving disease.

PMID: 34211499 Piras et al., 2021
Authors state approx 20% of cases are familial. MLPA study of patients with C3G (n = 103) and IC-MPGN (n = 96). Detected a deletion of the entire CFH, CFHR3, and CFHR1 in one patient with IC-MPGN, as well as CNVs in other CFH-related genes.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska changed review comment from: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.; to: PMID: 37615951 Meuleman et al., 2023
Cohort of 398 French patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102). 53 rare variants were identified, including variants in CFI, C3, and 30 variants in (57%) in CFH. 20/30 CFH variants were absent from gnomAD, and 24 were classified as Pathogenic according to ACMG criteria. Presence of a rare variant was associated with poor kidney survival. Plasma FH levels were low in 20 families, and normal in 10. 6/38 individuals were homozygous, 32 were heterozygous for CFH variants. Based on histology data, C3 glomerulopathy was confirmed in 32 patients, and Ig-MPGN in 6 individuals with CFH variants. Kidney failure (leading to dialysis or transplant) occured in 21/38 patients at time of report.

PMID: 31919107 Levine et al., 2020
Analysis of WGS data of 165 primary membranoproliferative GN cases and 10k controls from the UK. Authors found that the MPGN cohort was not enriched for rare variants in complement factors compared to the control group. Hence, they pose that "rather than resulting from a primary genetic disorder of complement alternative pathway regulation, in most cases PMG is actually an autoimmune disease."

The association between CFH and AR C3 glomerulonephritis has been classified as Definitive in ClinGen (Feb 2024). The gene is also associated with Semi Dominant atypical hemolytic-uremic syndrome (Definitive, July 2023). ClinGen accessed 4th June 2026.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska commented on gene: CFH: Comment on mode of inheritance: Meuleman et al., 2023 (PMID: 37615951) have reported more than 30 individuals with rare CFH variants and histologically confirmed C3 glomerulopathy or Ig-MPGN, with 21 patients with kidney failure at time of report. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Membranoproliferative glomerulonephritis including C3 glomerulopathy.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 CFH Ida Ertmanska reviewed gene: CFH: Rating: GREEN; Mode of pathogenicity: None; Publications: 37615951; Phenotypes: Complement factor H deficiency, OMIM:609814, {Hemolytic uremic syndrome, atypical, susceptibility to, 1}, OMIM:235400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v8.1 FTL Ida Ertmanska commented on gene: FTL: Comment on mode of inheritance: There are 2 unrelated cases reported with biallelic FTL variants and cataracts (1 case with onset at 35yrs, and 2 sibs with cataract onset at 17 & 20 yrs). As only 1 case matches the panel scope of childhood-onset, the MOI should remain as MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown, until more evidence emerges.
Iron metabolism disorders - NOT common HFE mutations v4.1 FTL Ida Ertmanska reviewed gene: FTL: Rating: GREEN; Mode of pathogenicity: None; Publications: 23300176, 23421845, 23940258, 32241646; Phenotypes: Hyperferritinemia-cataract syndrome, OMIM:600886, L-ferritin deficiency, dominant and recessive, OMIM:615604; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v8.1 FTL Ida Ertmanska changed review comment from: Reports of BIALLELIC cases:
PMID: 32241646 Ciftciler, Yılmaz & Buyukasik, 2020
Report of two sisters with FTL c.473T > C; p.Pro158Leu and unmeasurable serum ferritin levels, but normal on other iron measurements, no clinical symptoms apart from fatigue. 2 affected sibs were homozygous for the variant, unaffected parents and sister were heterozygous. No cataracts or neurological symptoms reported.

PMID: 23940258 Cozzi et al., 2013
Report of a 23-yr-old female patient affected by a homozygous variant in FTL: c.310G>T, p.(E104X); presented with idiopathic generalized seizures, and atypical restless leg syndrome (RLS). There was no FTL expression in patient fibroblasts - confirmed LoF. Increased iron incorporation, cytosolic iron deficiency, and oxidative damage were also seen in patient fibroblast experiments. No mention of cataracts

PMID: 23300176 Giansily-Blaizot et al., 2013
Proband = 54yo female with unexplained hyperferritinemia (initially 1960 μg/L), developed microcytic anemia; bilateral cataract diagnosed at age 35 yrs; she harboured a homozygous FTL variant NM_000146.3: c.-149G>C (+51G>C). Diagnosis of Hereditary hyperferritinemia cataract syndrome (HHCS). Family history of cataracts / visual impairment, but not sequenced.
The same variant "G51C" found previously in father-child pairs in a heterozygous state in PMID: 10759702 and PMID: 11704046. 1 allele reported in gnomAD v4.1.1.

PMID: 23421845 Luscieti et al., 2013
FTL mutations reported in 2 HHCS pedigrees: "Badalona" +36C>U - NM_000146.3]; c.-164C > T (found in both het and homozygous state) and the "Heidelberg" +52G>C mutation - NM_000146.3]; c.-148 G > C. Cataracts were diagnosed at 16-27yrs in these families.; to: Reports of BIALLELIC cases:
PMID: 32241646 Ciftciler, Yılmaz & Buyukasik, 2020
Report of two sisters with FTL c.473T > C; p.Pro158Leu and unmeasurable serum ferritin levels, but normal on other iron measurements, no clinical symptoms apart from fatigue. 2 affected sibs were homozygous for the variant, unaffected parents and sister were heterozygous. No cataracts or neurological symptoms reported.

PMID: 23940258 Cozzi et al., 2013
Report of a 23-yr-old female patient affected by a homozygous variant in FTL: c.310G>T, p.(E104X); presented with idiopathic generalized seizures, and atypical restless leg syndrome (RLS). There was no FTL expression in patient fibroblasts - confirmed LoF. Increased iron incorporation, cytosolic iron deficiency, and oxidative damage were also seen in patient fibroblast experiments. No mention of cataracts

PMID: 23300176 Giansily-Blaizot et al., 2013
Proband = 54yo female with unexplained hyperferritinemia (initially 1960 μg/L), developed microcytic anemia; bilateral cataract diagnosed at age 35 yrs; she harboured a homozygous FTL variant NM_000146.3: c.-149G>C (+51G>C). Diagnosis of Hereditary hyperferritinemia cataract syndrome (HHCS). Family history of cataracts / visual impairment, but not sequenced.
The same variant "G51C" found previously in father-child pairs in a heterozygous state in PMID: 10759702 and PMID: 11704046. 1 allele reported in gnomAD v4.1.1.

PMID: 23421845 Luscieti et al., 2013
FTL mutations reported in 2 HHCS pedigrees: "Badalona" +36C>U - NM_000146.3: c.-164C > T (found in both het and homozygous state) and the "Heidelberg" +52G>C mutation - NM_000146.3]; c.-148 G > C. Cataracts were diagnosed at 16-27yrs in these families.
"Badalona" +36C>U has 1 allele reported and "Heidelberg" +52G>C is not reported in gnomAD v4.1.1.
Bilateral congenital or childhood onset cataracts v8.1 FTL Ida Ertmanska changed review comment from: PMID: 32241646 Ciftciler, Yılmaz & Buyukasik, 2020
Report of two sisters with FTL c.473T > C; p.Pro158Leu and unmeasurable serum ferritin levels, but normal on other iron measurements, no clinical symptoms apart from fatigue. 2 affected sibs were homozygous for the variant, unaffected parents and sister were heterozygous. No cataracts or neurological symptoms reported.

PMID: 23940258 Cozzi et al., 2013
Report of a 23-yr-old female patient affected by a homozygous variant in FTL: c.310G>T, p.(E104X); presented with idiopathic generalized seizures, and atypical restless leg syndrome (RLS). There was no FTL expression in patient fibroblasts - confirmed LoF. Increased iron incorporation, cytosolic iron deficiency, and oxidative damage were also seen in patient fibroblast experiments.

PMID: 23300176 Giansily-Blaizot et al., 2013
Proband = 54yo female with unexplained hyperferritinemia (initially 1960 μg/L), developed microcytic anemia; bilateral cataract diagnosed at age 35 yrs; she harboured a homozygous FTL variant NM_000146.3: c.-149G>C (+51G>C). Diagnosis of Hereditary hyperferritinemia cataract syndrome (HHCS). Family history of cataracts / visual impairment, but not sequenced.
The same variant "G51C" found previously in father-child pairs in a heterozygous state in PMID: 10759702 and PMID: 11704046. 1 allele reported in gnomAD v4.1.1.

PMID: 23421845 Luscieti et al., 2013
FTL mutations reported in 2 HHCS pedigrees: "Badalona" +36C>U - NM_000146.3]; c.-164C > T (found in both het and homozygous state) and the "Heidelberg" +52G>C mutation - NM_000146.3]; c.-148 G > C. Cataracts were diagnosed at 16-27yrs in these families.; to: Reports of BIALLELIC cases:
PMID: 32241646 Ciftciler, Yılmaz & Buyukasik, 2020
Report of two sisters with FTL c.473T > C; p.Pro158Leu and unmeasurable serum ferritin levels, but normal on other iron measurements, no clinical symptoms apart from fatigue. 2 affected sibs were homozygous for the variant, unaffected parents and sister were heterozygous. No cataracts or neurological symptoms reported.

PMID: 23940258 Cozzi et al., 2013
Report of a 23-yr-old female patient affected by a homozygous variant in FTL: c.310G>T, p.(E104X); presented with idiopathic generalized seizures, and atypical restless leg syndrome (RLS). There was no FTL expression in patient fibroblasts - confirmed LoF. Increased iron incorporation, cytosolic iron deficiency, and oxidative damage were also seen in patient fibroblast experiments. No mention of cataracts

PMID: 23300176 Giansily-Blaizot et al., 2013
Proband = 54yo female with unexplained hyperferritinemia (initially 1960 μg/L), developed microcytic anemia; bilateral cataract diagnosed at age 35 yrs; she harboured a homozygous FTL variant NM_000146.3: c.-149G>C (+51G>C). Diagnosis of Hereditary hyperferritinemia cataract syndrome (HHCS). Family history of cataracts / visual impairment, but not sequenced.
The same variant "G51C" found previously in father-child pairs in a heterozygous state in PMID: 10759702 and PMID: 11704046. 1 allele reported in gnomAD v4.1.1.

PMID: 23421845 Luscieti et al., 2013
FTL mutations reported in 2 HHCS pedigrees: "Badalona" +36C>U - NM_000146.3]; c.-164C > T (found in both het and homozygous state) and the "Heidelberg" +52G>C mutation - NM_000146.3]; c.-148 G > C. Cataracts were diagnosed at 16-27yrs in these families.
Bilateral congenital or childhood onset cataracts v8.1 FTL Ida Ertmanska edited their review of gene: FTL: Changed publications to: 23300176, 23421845, 23940258, 32241646; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bilateral congenital or childhood onset cataracts v8.1 FTL Ida Ertmanska changed review comment from: PMID: 23940258 Cozzi et al., 2013

PMID: 23300176 Giansily-Blaizot et al., 2013
Proband = 54yo female with unexplained hyperferritinemia (initially 1960 μg/L), developed microcytic anemia; bilateral cataract diagnosed at age 35 yrs; she harboured a homozygous FTL variant NM_000146.3: c.-149G>C (+51G>C). Diagnosis of Hereditary hyperferritinemia cataract syndrome (HHCS). Family history of cataracts / visual impairment, but not sequenced.
The same variant "G51C" found previously in father-child pairs in a heterozygous state in PMID: 10759702 and PMID: 11704046. 1 allele reported in gnomAD v4.1.1.

PMID: 23421845 Luscieti et al., 2013
FTL mutations reported in 2 HHCS pedigrees: "Badalona" +36C>U - NM_000146.3]; c.-164C > T (found in both het and homozygous state) and the "Heidelberg" +52G>C mutation - NM_000146.3]; c.-148 G > C. Cataracts were diagnosed at 16-27yrs in these families.; to: PMID: 32241646 Ciftciler, Yılmaz & Buyukasik, 2020
Report of two sisters with FTL c.473T > C; p.Pro158Leu and unmeasurable serum ferritin levels, but normal on other iron measurements, no clinical symptoms apart from fatigue. 2 affected sibs were homozygous for the variant, unaffected parents and sister were heterozygous. No cataracts or neurological symptoms reported.

PMID: 23940258 Cozzi et al., 2013
Report of a 23-yr-old female patient affected by a homozygous variant in FTL: c.310G>T, p.(E104X); presented with idiopathic generalized seizures, and atypical restless leg syndrome (RLS). There was no FTL expression in patient fibroblasts - confirmed LoF. Increased iron incorporation, cytosolic iron deficiency, and oxidative damage were also seen in patient fibroblast experiments.

PMID: 23300176 Giansily-Blaizot et al., 2013
Proband = 54yo female with unexplained hyperferritinemia (initially 1960 μg/L), developed microcytic anemia; bilateral cataract diagnosed at age 35 yrs; she harboured a homozygous FTL variant NM_000146.3: c.-149G>C (+51G>C). Diagnosis of Hereditary hyperferritinemia cataract syndrome (HHCS). Family history of cataracts / visual impairment, but not sequenced.
The same variant "G51C" found previously in father-child pairs in a heterozygous state in PMID: 10759702 and PMID: 11704046. 1 allele reported in gnomAD v4.1.1.

PMID: 23421845 Luscieti et al., 2013
FTL mutations reported in 2 HHCS pedigrees: "Badalona" +36C>U - NM_000146.3]; c.-164C > T (found in both het and homozygous state) and the "Heidelberg" +52G>C mutation - NM_000146.3]; c.-148 G > C. Cataracts were diagnosed at 16-27yrs in these families.
Bilateral congenital or childhood onset cataracts v8.1 FTL Ida Ertmanska reviewed gene: FTL: Rating: GREEN; Mode of pathogenicity: None; Publications: 23300176, 23421845, 23940258; Phenotypes: Hyperferritinemia-cataract syndrome, OMIM:600886, L-ferritin deficiency, dominant and recessive, OMIM:615604; Mode of inheritance: None
Fetal anomalies v7.11 GRHL2 Ida Ertmanska edited their review of gene: GRHL2: Changed rating: AMBER
Fetal anomalies v7.11 GRHL2 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: GRHL2.
Monogenic hearing loss v6.16 COL11A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant hearing loss / Marshall syndrome / Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with severe hearing loss. These cases do not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. 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.; to: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant hearing loss / Marshall syndrome / Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with severe hearing loss. These cases do not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. 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.
Retinal disorders v9.4 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic. Authors pose that LOF variants lead to dominant hearing loss.
Retinal disorders v9.4 COL11A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variabel reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome / Marshall syndrome / isolated hearing loss, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variable reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Monogenic hearing loss v6.16 COL11A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant hearing loss, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with severe hearing loss. These cases do not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. 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.; to: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant hearing loss / Marshall syndrome / Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with severe hearing loss. These cases do not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. 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.
Retinal disorders v9.4 COL11A1 Ida Ertmanska Publications for gene: COL11A1 were set to 10486316; 17318849
Retinal disorders v9.3 COL11A1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: COL11A1.
Retinal disorders v9.3 COL11A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variabel reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. 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.; to: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variabel reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Retinal disorders v9.3 COL11A1 Ida Ertmanska commented on gene: COL11A1: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant Stickler syndrome, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with more severe presentation. Variabel reported ocular features included retinal atrophy, retinal tears, high myopia, unilateral retinal detachment, hypermetropia, and cataract. These cases did not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. 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.
Monogenic hearing loss v6.16 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss. ; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - apart from inner ear cartilage - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.
Retinal disorders v9.3 COL11A1 Ida Ertmanska reviewed gene: COL11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32578940, 31833174, 23922384, 23026214, 21035103; Phenotypes: Deafness, autosomal dominant 37, 618533, Marshall syndrome, 154780, Stickler syndrome, type II, 604841, Fibrochondrogenesis 1, 228520; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v6.16 COL11A1 Ida Ertmanska edited their review of gene: COL11A1: Added comment: Comment on mode of inheritance: While heterozygous LOF variants in COL11A1 are known to cause dominant hearing loss, there are also more than 3 unrelated cases reported with biallelic COL11A1 variants and Stickler syndrome with severe hearing loss. These cases do not present with skeletal dysplasia, as they had variants in alternatively spliced exon 9 on one or both alleles (exon 9 is not expressed in mature chondrocytes). Heterozygous parents of these individuals were either asymptomatic, or had mild myopia / mild hearing loss. 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.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Monogenic hearing loss v6.16 COL11A1 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: COL11A1.
Tag Q2_26_MOI tag was added to gene: COL11A1.
Monogenic hearing loss v6.16 COL11A1 Ida Ertmanska Publications for gene: COL11A1 were set to 30245514; 17236192
Skeletal dysplasia v9.13 LOXL3 Ida Ertmanska edited their review of gene: LOXL3: Changed rating: AMBER
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband, European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss. ; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C which affects splicing of exon 9 (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."
"While exon 9 is expressed in both vitreous and immature chondrocytes, it is not expressed in mature chondrocytes" - so any variants affecting exon 9 do not cause fibrochondrogenesis, but a Stickler syndrome phenotype with severe hearing loss.

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous exon 9 c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband of European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: COL11A1.
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband, European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss. ; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia. Parents unaffected, only mild myopia seen in the father.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband, European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska edited their review of gene: COL11A1: Changed publications to: 32578940, 31833174, 23922384, 23026214, 21035103
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska changed review comment from: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C.
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively.
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.; to: PMID: 32578940 Nixon et al., 2020
Female patient with clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. She was comp het for COL11A1 variants: a de novo in frame deletion of COL11A1 (c.4109_4126del) and splice variant c.1245+2T>C (inherited from unaffected mother).
Her parents were nonconsanguineous and had no eye, hearing, joint, or palate abnormalities.
Author explanation of inheritance: "The de novo deletion alone would be expected to result in dominant type 2 Stickler syndrome, but missplicing of exon 9 leads to additional severe hearing loss."

PMID: 31833174 Abreu et al., 2020
3yo male proband with pontocerebellar hypoplasia caused by a homozygous AMPD2 p.[Pro734Leu] variant, and Stickler syndrome 2, likely caused by a homozygous COL11A1 c.1168G > T, p.[Glu390Ter] change. He presented with high myopia, mild-to-moderate hearing loss, as well as AMPD2-related profound motor and language delay.

PMID: 23922384 Richards et al., 2013
3 families with recessive form of type 2 Stickler syndrome characterised by particularly profound hearing loss. Heterozygous parents either had minor signs associated with Stickler syndrome, or were asymptomatic.
F1 - proband with cleft palate, hypermetropia, and profound deafness, was comp het for COL11A1 variants: (c.1191delT, p.Asn398Metfs*19) and (c.4259G>T, p.Gly1420Val) - exon 9 and 58, respectively. Age-compatible hearing loss in the mother, and mild-to-moderate hearing loss in the father
F2 - proband with high myopia, Pierre Robin sequence, and profound hearing loss, similarly affected sibling. Comp het for COL11A1 c.1421dupC, p.Gly475Argfs*9 in exon 13 and c.991-24A>G in intron 8 - creating an alternative exon 9 acceptor splice site.
F3 - girl with hearing loss diagnosed at 5 weeks, and retinal dystrophy noted at 2 yrs, also had clinical joint laxity. Parents unaffected, no hearing loss. Comp het c.2607A>G, p.Ala869Ala (shown to affect splicing) and c.5398G>T, p.Gly1800Cys.

PMID: 23026214 Alzahrani et al., 2012
6yo patient with homozygous c.1191delT, p.(Asn398Metfs*19) variant in COL11A1; phenotype: unilateral retinal detachment, SNHL, cleft palate, flat midface, micrognathia.

PMID: 21035103 Tompson et al., 2010
2 individuals with Fibrochondrogenesis (severe skeletal dysplasia).
Family 1 - proband, European descent, comp het for COL11A1 variants c.1786dupG, (p.Ala596GlyfsX8), and c.3124G>A, (p.Gly1042Arg); presented with skeletal dysplasia (no note of hearing assessment); mother had myopia and normal hearing, father had hearing loss and wore glasses since childhood.
Family 2 - male proband (European and African American descent) comp het for COL11A1 c.2386G>C (p.Gly796Arg) and c.3943G>T, (p.Gly1315X) variants; he has fibrochondrogenesis, mild-moderate hearing loss, high myopia and left cataract. Father had mild hearing loss, mother - mild myopia (normal hearing), otherwise asymptomatic.
Authors pose that LOF variants lead to dominant hearing loss.
Monogenic hearing loss v6.15 COL11A1 Ida Ertmanska reviewed gene: COL11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32578940, 23922384; Phenotypes: Deafness, autosomal dominant 37, 618533, Marshall syndrome, 154780, Stickler syndrome, type II, 604841, Fibrochondrogenesis 1, 228520; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.1 DYSF Cassandra Smith reviewed gene: DYSF: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35962550, 39511170; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myopathy v7.44 TK2 Achchuthan Shanmugasundram Classified gene: TK2 as Amber List (moderate evidence)
Congenital myopathy v7.44 TK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are numerous patients reported in literature with biallelic variants in TK2 and mitochondrial myopathy. More than 25 cases have been reported with rapidly progressive infantile-onset (<1year of age) muscle weakness, usually leading to respiratory failure before age 3. Based on available evidence TK2 should be promoted to Green for Congenital myopathy panel at the next GMS update.
Congenital myopathy v7.44 TK2 Achchuthan Shanmugasundram Gene: tk2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.43 TK2 Achchuthan Shanmugasundram Phenotypes for gene: TK2 were changed from to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560; mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301
Congenital myopathy v7.42 TK2 Achchuthan Shanmugasundram Publications for gene: TK2 were set to
Congenital myopathy v7.41 TK2 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: TK2.
Tag Q2_26_NHS_review tag was added to gene: TK2.
Congenital myopathy v7.41 TK2 Achchuthan Shanmugasundram reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18819985, 38544965, 40098049; Phenotypes: Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560, mitochondrial DNA depletion syndrome, myopathic form, MONDO:0012301; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.18 SYP Julie Evans reviewed gene: SYP: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 19377476; Phenotypes: ; 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 v7.11 DST Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #621510 & 621511) and the OMIM record was last accessed on 01 June 2026.
Fetal anomalies v7.11 DST Achchuthan Shanmugasundram Phenotypes for gene: DST were changed from Arthrogryposis multiplex congenita, MONDO:0015168; arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952 to Congenital myopathy 29 with contractures, OMIM:621510; congenital myopathy 29 with contractures, MONDO:0981030; Lethal congenital contracture syndrome 12, OMIM:621511; lethal congenital contracture syndrome 12, MONDO:0981031
Arthrogryposis v10.7 DST Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #621510 & 621511) and the OMIM record was last accessed on 01 June 2026.
Arthrogryposis v10.7 DST Achchuthan Shanmugasundram Phenotypes for gene: DST were changed from arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952 to Congenital myopathy 29 with contractures, OMIM:621510; congenital myopathy 29 with contractures, MONDO:0981030; Lethal congenital contracture syndrome 12, OMIM:621511; lethal congenital contracture syndrome 12, MONDO:0981031
Paediatric or syndromic cardiomyopathy v8.2 DST Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with Congenital myopathy 29 with contractures in OMIM (MIM #621510) and the OMIM record was last accessed on 01 June 2026.
Paediatric or syndromic cardiomyopathy v8.2 DST Achchuthan Shanmugasundram Phenotypes for gene: DST were changed from arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952 to Congenital myopathy 29 with contractures, OMIM:621510; congenital myopathy 29 with contractures, MONDO:0981030
Hereditary neuropathy or pain disorder v8.4 DST Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with Neuropathy, hereditary sensory and autonomic, type VI in OMIM (MIM #614653) and the OMIM record was last accessed on 01 June 2026.
Hereditary neuropathy or pain disorder v8.4 DST Achchuthan Shanmugasundram Phenotypes for gene: DST were changed from Hereditary Sensory and Autonomic Neuropathy, Type VI; ?Neuropathy, hereditary sensory and autonomic, type VI to Neuropathy, hereditary sensory and autonomic, type VI, OMIM:614653; hereditary sensory and autonomic neuropathy type 6, MONDO:0013839
Congenital myopathy v7.41 DST Achchuthan Shanmugasundram Tag Q2_26_NHS_review tag was added to gene: DST.
Congenital myopathy v7.41 DST Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with Congenital myopathy 29 with contractures in OMIM (MIM #621510) and the OMIM record was last accessed on 01 June 2026.
Congenital myopathy v7.41 DST Achchuthan Shanmugasundram Phenotypes for gene: DST were changed from arthrogryposis, MONDO:0859248; cardiomyopathy, MONDO:0004994; congenital myopathy, MONDO:0019952 to Congenital myopathy 29 with contractures, OMIM:621510; congenital myopathy 29 with contractures, MONDO:0981030
Congenital myopathy v7.40 HRAS Achchuthan Shanmugasundram Classified gene: HRAS as Amber List (moderate evidence)
Congenital myopathy v7.40 HRAS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least six unrelated cases reported with monoallelic HRAS variants and congenital myopathy with excess of muscle spindles (CMEMS). Hence, this gene can be promoted to green rating in the next GMS update.
Congenital myopathy v7.40 HRAS Achchuthan Shanmugasundram Gene: hras has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.39 HRAS Achchuthan Shanmugasundram Phenotypes for gene: HRAS were changed from Costello syndrome, OMIM:218040; Congenital myopathy with excess of muscle spindles, OMIM:218040 to Congenital myopathy with excess of muscle spindles, OMIM:218040; Costello syndrome, OMIM:218040; Costello syndrome, MONDO:0009026
Congenital myopathy v7.38 HRAS Achchuthan Shanmugasundram Publications for gene: HRAS were set to 17412879
Congenital myopathy v7.37 HRAS Achchuthan Shanmugasundram Mode of inheritance for gene: HRAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.36 HRAS Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: HRAS.
Tag Q2_26_NHS_review tag was added to gene: HRAS.
Congenital myopathy v7.36 HRAS Achchuthan Shanmugasundram reviewed gene: HRAS: Rating: GREEN; Mode of pathogenicity: None; Publications: 17412879, 25070542, 26001911; Phenotypes: Congenital myopathy with excess of muscle spindles, OMIM:218040, Costello syndrome, OMIM:218040, Costello syndrome, MONDO:0009026; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Confirmed Fanconi anaemia or Bloom syndrome v2.15 XRCC2 Arina Puzriakova Publications for gene: XRCC2 were set to 22232082; 27208205
Pigmentary skin disorders v5.3 XRCC2 Arina Puzriakova Publications for gene: XRCC2 were set to 22232082; 27208205
Tubulointerstitial kidney disease v3.33 MT-TV Una Conka-Priedeslaipa gene: MT-TV was added
gene: MT-TV was added to Tubulointerstitial kidney disease. Sources: Literature
Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL
Publications for gene: MT-TV were set to https://www.sciencedirect.com/science/article/pii/S246802492602810X
Added comment: In 27,747 participants from the Mount Sinai Million Health Discoveries Program, an ancestrally diverse biobank with whole-exome sequencing and linked electronic health records, the MT-TV m.1630A>G variant was observed in 4 individuals with kidney disease and 6 without kidney disease and was significantly associated with kidney disease risk (OR = 5.63, 95% CI: 1.28–22.89, P = 0.016).
Sources: Literature
Familial melanoma v2.5 CHEK2 Riyaad Aungraheeta gene: CHEK2 was added
gene: CHEK2 was added to Familial melanoma. Sources: Literature
Mode of inheritance for gene: CHEK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CHEK2 were set to PMID: 42177185
Phenotypes for gene: CHEK2 were set to Mucosal melanoma
Review for gene: CHEK2 was set to AMBER
Added comment: The CHEK2 c.1100delC variant was enriched in this retrospective cohort of mucosal melanoma patients compared to population controls (OR 6.7; 95% CI 1.8–17.5).
Sources: Literature
Familial melanoma v2.5 MITF Riyaad Aungraheeta gene: MITF was added
gene: MITF was added to Familial melanoma. Sources: Literature
Mode of inheritance for gene: MITF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MITF were set to PMID: 42177185
Phenotypes for gene: MITF were set to Mucosal melanoma
Review for gene: MITF was set to AMBER
Added comment: The MITF E318K variant was enriched in this retrospective cohort of mucosal melanoma patients compared to population controls (OR 6.0; 95% CI 2.2–13.2).
Sources: Literature
Congenital myopathy v7.36 CNTN1 Achchuthan Shanmugasundram changed review comment from: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).; to: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia. The siblings died after 3 and 5 days after birth.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).
Congenital myopathy v7.36 CNTN1 Achchuthan Shanmugasundram Classified gene: CNTN1 as Amber List (moderate evidence)
Congenital myopathy v7.36 CNTN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are two unrelated families reported with biallelic CNTN1 variants, myopathy was only reported in one. The siblings from the second family died after 3 and 5 days after birth. Both families were reported with fetal akinesia. There is also functional evidence available from cntn1 null mouse which showed progressive muscle weakness. Hence, this gene can only be rated amber on this panel with current evidence (one family and functional evidence).
Congenital myopathy v7.36 CNTN1 Achchuthan Shanmugasundram Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.35 CNTN1 Achchuthan Shanmugasundram Phenotypes for gene: CNTN1 were changed from Myopathy, congenital, Compton-North, OMIM:612540 to Congenital myopathy 12, OMIM:612540
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram edited their review of gene: CNTN1: Changed publications to: 19026398, 32779773; Changed phenotypes to: Congenital myopathy 12, OMIM:612540
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram changed review comment from: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).; to: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia and with homozygous deletion of exons 2-15 and 18-19. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram edited their review of gene: CNTN1: Changed rating: AMBER
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram Deleted their comment
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram commented on gene: CNTN1: PMID:19026398 (2008) reported four individuals from a consanguineous family of Egyptian descent with a lethal congenital myopathy characterised by secondary loss of β2-syntrophin and α-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. The patients were identified with a homozygous thymidine duplication (c.871dupT) within exon 8 predicted to result in a reading frameshift introducing a premature stop codon (S291fsX296). There is also functional evidence available from cntn1 null mouse, which presented with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family.

PMID:32779773 (2020) reported two siblings presenting parentally with fetal akinesia. Other features included micrognathia and skin oedema in one, and pleural and pericardial effusions and skin oedema in the other. Both siblings had arthrogryposis and lung hypoplasia.

This gene has been associated with relevant phenotype in OMIM (MIM #612540, last accessed 28 May 2026).
Congenital myopathy v7.34 CNTN1 Achchuthan Shanmugasundram reviewed gene: CNTN1: Rating: GREEN; Mode of pathogenicity: None; Publications: Congenital myopathy 12, OMIM:612540; Phenotypes: 19026398, 32779773; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.13 HMGCS1 Achchuthan Shanmugasundram Classified gene: HMGCS1 as Amber List (moderate evidence)
Skeletal dysplasia v9.13 HMGCS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with biallelic HMGCS1 variants and with congenital myopathy with rigid spine. All cases also had scoliosis. Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Skeletal dysplasia v9.13 HMGCS1 Achchuthan Shanmugasundram Gene: hmgcs1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.12 HMGCS1 Achchuthan Shanmugasundram gene: HMGCS1 was added
gene: HMGCS1 was added to Skeletal dysplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: HMGCS1.
Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGCS1 were set to 39531736
Phenotypes for gene: HMGCS1 were set to Congenital myopathy 28 with rigid spine, OMIM:621433; congenital myopathy 28 with rigid spine, MONDO:0980756
Review for gene: HMGCS1 was set to GREEN
Added comment: PMID:39531736 (2025) reported biallelic variants in HMGCS1 gene identified via whole exome and genome sequencing in five patients from four unrelated families with rigid spine syndrome. The identified variants included 6 missense variants and one 2-basepair deletion resulting in a frameshift and early termination. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated and muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.

Three of the four functionally analysed variants exhibited reduced thermal stability, and two of them showed subtle changes in enzymatic activity compared to the wildtype. Hmgcs1 mutant zebrafish displayed severe early defects and the four variants tested have reduced function compared to wild-type HMGCS1 in zebrafish rescue assays. In addition, potential for mevalonic acid supplementation to reduce phenotypic severity in mutant zebrafish was also demonstrated.

This gene has been associated with relevant phenotype in OMIM (MIM #62143) and the OMIM record was last accessed on 28 May 2026.
Sources: Literature
Clefting v7.5 JPH1 Achchuthan Shanmugasundram Classified gene: JPH1 as Amber List (moderate evidence)
Clefting v7.5 JPH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are four unrelated patients reported with congenital myopathy and biallelic JPH1 variants, only two of them were reported with cleft palate as one of the phenotypes. Hence, this gene can only be rated amber with the current evidence.
Clefting v7.5 JPH1 Achchuthan Shanmugasundram Gene: jph1 has been classified as Amber List (Moderate Evidence).
Clefting v7.4 JPH1 Achchuthan Shanmugasundram gene: JPH1 was added
gene: JPH1 was added to Clefting. Sources: Literature
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy 25, OMIM:620964; congenital myopathy 25, MONDO:0975808
Review for gene: JPH1 was set to AMBER
Added comment: PMID:39209426 (2024) reported four unrelated patients with congenital myopathy and they had similar clinical presentation with prominent facial, ocular and bulbar features. The disease onset was in neonatal period and had hypotonia, poor feeding, cleft palate and talipes. Four different homozygous loss-of-function variants were reported in these patients either by whole-exome or whole-genome sequencing. Cleft palate was reported in two of these patients and arched palate in one.

This gene has been associated with relevant phenotypes in OMIM (MIM #620964, last accessed 28 May 2026) and in Gene2Phenotype (with 'moderate' confidence rating on the DD panel).
Sources: Literature
Skeletal dysplasia v9.11 JPH1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: JPH1.
Skeletal dysplasia v9.11 JPH1 Achchuthan Shanmugasundram Classified gene: JPH1 as Amber List (moderate evidence)
Skeletal dysplasia v9.11 JPH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated patients reported with congenital myopathy and biallelic JPH1 variants. All patients had spine involvement (kyphoscoliosis, scoliosis or lumbar lordosis). Hence, this gene can be promoted to green rating on Skeletal dysplasia panel in the next GMS update.
Skeletal dysplasia v9.11 JPH1 Achchuthan Shanmugasundram Gene: jph1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.10 JPH1 Achchuthan Shanmugasundram edited their review of gene: JPH1: Changed rating: GREEN
Skeletal dysplasia v9.10 JPH1 Achchuthan Shanmugasundram gene: JPH1 was added
gene: JPH1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy 25, OMIM:620964; congenital myopathy 25, MONDO:0975808
Review for gene: JPH1 was set to AMBER
Added comment: PMID:39209426 (2024) reported four unrelated patients with congenital myopathy and they had similar clinical presentation with prominent facial, ocular and bulbar features. The disease onset was in neonatal period and had hypotonia, poor feeding, cleft palate and talipes. Four different homozygous loss-of-function variants were reported in these patients either by whole-exome or whole-genome sequencing. Kyphoscoliosis and rigid spine was reported in patient 1, dorsal scoliosis, lumbar lordosis and winged scapulae in patient 2, mild lumbar lordosis in patient 3 and mild scoliosis in patient 4.

This gene has been associated with relevant phenotypes in OMIM (MIM #620964, last accessed 28 May 2026) and in Gene2Phenotype (with 'moderate' confidence rating on the DD panel).
Sources: Literature
Congenital myopathy v7.34 JPH1 Achchuthan Shanmugasundram Classified gene: JPH1 as Amber List (moderate evidence)
Congenital myopathy v7.34 JPH1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated individuals with Congenital myopathy 25 and with biallelic JPH1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Congenital myopathy v7.34 JPH1 Achchuthan Shanmugasundram Gene: jph1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.33 JPH1 Achchuthan Shanmugasundram Phenotypes for gene: JPH1 were changed from to Congenital myopathy 25, OMIM:620964; congenital myopathy 25, MONDO:0975808
Congenital myopathy v7.32 JPH1 Achchuthan Shanmugasundram Publications for gene: JPH1 were set to
Congenital myopathy v7.31 JPH1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: JPH1.
Tag Q2_26_NHS_review tag was added to gene: JPH1.
Congenital myopathy v7.31 JPH1 Achchuthan Shanmugasundram reviewed gene: JPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39209426; Phenotypes: Congenital myopathy 25, OMIM:620964, congenital myopathy 25, MONDO:0975808; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.31 HMGCS1 Achchuthan Shanmugasundram Classified gene: HMGCS1 as Amber List (moderate evidence)
Congenital myopathy v7.31 HMGCS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Anna Sarkozy, there is sufficient evidence available (four unrelated families and functional evidence) for the association of biallelic HMGCS1 variants with congenital myopathy. Hence, this gene can be promoted to green rating in the next GMS update.
Congenital myopathy v7.31 HMGCS1 Achchuthan Shanmugasundram Gene: hmgcs1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.30 HMGCS1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: HMGCS1.
Tag Q2_26_NHS_review tag was added to gene: HMGCS1.
Congenital myopathy v7.30 HMGCS1 Achchuthan Shanmugasundram Phenotypes for gene: HMGCS1 were changed from to Congenital myopathy 28 with rigid spine, OMIM:621433; congenital myopathy 28 with rigid spine, MONDO:0980756
Congenital myopathy v7.29 HMGCS1 Achchuthan Shanmugasundram Publications for gene: HMGCS1 were set to
Congenital myopathy v7.28 HMGCS1 Achchuthan Shanmugasundram reviewed gene: HMGCS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39531736; Phenotypes: Congenital myopathy 28 with rigid spine, OMIM:621433, congenital myopathy 28 with rigid spine, MONDO:0980756; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.28 CACNA1H Achchuthan Shanmugasundram Classified gene: CACNA1H as Amber List (moderate evidence)
Congenital myopathy v7.28 CACNA1H Achchuthan Shanmugasundram Added comment: Comment on list classification: Although there are three unrelated individuals reported with biallelic CACNA1H variants so far, only one of them was reported with congenital amyotrophy/ myopathy. There is also functional evidence available in support of the association. Hence, this gene can only be rated amber with current evidence on this panel.
Congenital myopathy v7.28 CACNA1H Achchuthan Shanmugasundram Gene: cacna1h has been classified as Amber List (Moderate Evidence).
Congenital myopathy v7.27 CACNA1H Achchuthan Shanmugasundram Publications for gene: CACNA1H were set to
Congenital myopathy v7.26 CACNA1H Achchuthan Shanmugasundram Mode of inheritance for gene: CACNA1H was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.25 CACNA1H Achchuthan Shanmugasundram reviewed gene: CACNA1H: Rating: AMBER; Mode of pathogenicity: None; Publications: 25773295, 31070086, 41272325; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v4.33 DSPP Ida Ertmanska changed review comment from: PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025
Lit review of 322 cases with non-syndromic dentinogenesis imperfecta (DI - characterized clinically by amber or gray-yellow opalescent tooth discoloration, obliteration of pulp chambers and root canals, and attrition. Both deciduous and permanent teeth are affected (PMID: 18456718 Song et al., 2008).
DSPP mutations were the most frequent, with with 59 documented variants from 37 publications. 34/59 variants were in exon 5 of DSPP.
Sources: Literature; to: PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025
Lit review of 322 cases with non-syndromic dentinogenesis imperfecta (DI - characterized clinically by amber or gray-yellow opalescent tooth discoloration, obliteration of pulp chambers and root canals, and attrition. Both deciduous and permanent teeth are affected (PMID: 18456718 Song et al., 2008)).
DSPP mutations were the most frequent, with 59 documented variants from 37 publications. 34/59 variants were in exon 5 of DSPP.
Sources: Literature
Optic neuropathy v6.42 MT-ATP6 Achchuthan Shanmugasundram Tag Q2_26_expert_review tag was added to gene: MT-ATP6.
Optic neuropathy v6.42 MT-ATP6 Achchuthan Shanmugasundram Phenotypes for gene: MT-ATP6 were changed from Leber optic atrophy; 535000; neurogenic weakness, ataxia, and retinitis pigmentosa; retinopathy; NARP syndrome, MONDO:0010794 to NARP syndrome, MONDO:0010794
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska changed review comment from: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are common and homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.; to: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are common and homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska changed review comment from: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.; to: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are common and homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska changed review comment from: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes. Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.; to: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska commented on gene: MT-ATP6: Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes. Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.
Optic neuropathy v6.41 MT-ATP6 Ida Ertmanska Phenotypes for gene: MT-ATP6 were changed from Leber optic atrophy; 535000; neurogenic weakness, ataxia, and retinitis pigmentosa; retinopathy to Leber optic atrophy; 535000; neurogenic weakness, ataxia, and retinitis pigmentosa; retinopathy; NARP syndrome, MONDO:0010794
Optic neuropathy v6.40 MT-ATP6 Ida Ertmanska Publications for gene: MT-ATP6 were set to 7726182; 10676807; 26448634; 26252090; 24118886 (functional evidence); 23266623
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska Tag Q2_26_demote_red tag was added to gene: MT-ATP6.
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska edited their review of gene: MT-ATP6: Changed phenotypes to: NARP syndrome, MONDO:0010794
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska edited their review of gene: MT-ATP6: Changed rating: RED; Changed publications to: 7726182, 24986921, 26252090, 26448634, 41234160; Changed mode of inheritance: MITOCHONDRIAL
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 26252090 Gao et al., 2015
Report of two Chinese families with Leber's hereditary optic neuropathy, with penetrance of 12.5% and 30.0% in the two families. Only mitochondrial genome was sequenced - this detected homoplasmic T8821G mutation in MT-ATP6, and distinct sets of polymorphisms belonging to haplogroups M10a.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.; to: PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 26448634 Widgren et al., 2015
Nine rare mutations in MT-ATP6 were identified in seven patients, of whom four manifested with retinopathy and three had clusters of MT-ATP6 mutations.
Variant m.8842A>G (MT-ATP6) found in an optic neuropathy patient (haplogroup H2). 2 other MT-ATP6 variants found in nystagmus cohort, and 4 other variants were unique to the retinal degeneration group. The m.8842A>G was not predicted to affect protein function. 128/56430 individuals are homoplasmic in gnomAD v3.1.2 (most in haplogroup H) - B/LB in ClinVar.

PMID: 26252090 Gao et al., 2015
Report of two Chinese families with Leber's hereditary optic neuropathy, with penetrance of 12.5% and 30.0% in the two families. Only mitochondrial genome was sequenced - this detected homoplasmic T8821G mutation in MT-ATP6, and distinct sets of polymorphisms belonging to haplogroups M10a.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.; to: PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 26252090 Gao et al., 2015
Report of two Chinese families with Leber's hereditary optic neuropathy, with penetrance of 12.5% and 30.0% in the two families. Only mitochondrial genome was sequenced - this detected homoplasmic T8821G mutation in MT-ATP6, and distinct sets of polymorphisms belonging to haplogroups M10a.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.
Optic neuropathy v6.39 MT-ATP6 Ida Ertmanska commented on gene: MT-ATP6
Optic neuropathy v6.39 NDUFS1 Ida Ertmanska Publications for gene: NDUFS1 were set to
Optic neuropathy v6.38 NDUFS1 Ida Ertmanska Phenotypes for gene: NDUFS1 were changed from Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226 to Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226
Optic neuropathy v6.37 NDUFS1 Ida Ertmanska Classified gene: NDUFS1 as Amber List (moderate evidence)
Optic neuropathy v6.37 NDUFS1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases reported with biallelic NDUFS1 variants and optic neuropathy (LHON-like or syndromic CI-deficiency presentation). Hence, this gene should be promoted to Green at the next update.
Optic neuropathy v6.37 NDUFS1 Ida Ertmanska Gene: ndufs1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.36 NDUFS1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFS1.
Optic neuropathy v6.36 NDUFS1 Ida Ertmanska reviewed gene: NDUFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 11349233, 39423307; Phenotypes: Mitochondrial complex I deficiency, nuclear type 5, OMIM:618226; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.36 NDUFAF5 Ida Ertmanska changed review comment from: Saada et al., 2012 PMID: 21607760
P1 - Male, Ashkenazi Jewish ancestry - diagnosed with Leigh syndrome, optic atrophy noted at 26 months. Homozygous for NDUFAF5:c.749G>T, p.Gly250Val.

Simon et al., 2020, PMID: 30473481
P2 - Female, Taiwanese descent - presented at twenty-seven months of age with strabismus, followed by ptosis and vomiting during an intercurrent illness. Ophthalmological testing at 7yrs old revealed nystagmus as well as optic neuritis.

Mansukhani et al. 2021, PMID: 32918965
Proband with LHONplus phenotype, compound het for nonsense & missense variants.

Chen et al. 2024, PMID: 36580434
Proband with LHON-like phenotype with cognitive impairment, hom for frameshift NDUFAF5 variant c.1004_1007del, p.N335Tfs*37 (asymptomatic parents both het).
Sources: Literature; to: Saada et al., 2012 PMID: 21607760
P1 - Male, Ashkenazi Jewish ancestry - diagnosed with Leigh syndrome, optic atrophy noted at 26 months. Homozygous for NDUFAF5:c.749G>T, p.Gly250Val.

Simon et al., 2020, PMID: 30473481
P2 - Female, Taiwanese descent - presented at twenty-seven months of age with strabismus, followed by ptosis and vomiting during an intercurrent illness. Ophthalmological testing at 7yrs old revealed nystagmus as well as optic neuritis.

Mansukhani et al. 2021, PMID: 32918965
Proband with LHONplus phenotype, compound het for nonsense & missense variants in NDUFAF5: c.24G>A, p.(Trp8*) and c.827G>A, p.(Arg276Gln),

Chen et al. 2024, PMID: 36580434
Proband with LHON-like phenotype with cognitive impairment, hom for frameshift NDUFAF5 variant c.1004_1007del, p.N335Tfs*37 (asymptomatic parents both het).

NDUFAF5 is associated with AR Mitochondrial complex I deficiency, nuclear type 16, OMIM:618238 (accessed 27th May 2026).
Sources: Literature
Optic neuropathy v6.36 NDUFAF5 Ida Ertmanska Classified gene: NDUFAF5 as Amber List (moderate evidence)
Optic neuropathy v6.36 NDUFAF5 Ida Ertmanska Added comment: Comment on list classification: There are at least 4 unrelated probands reported in literature with biallelic NDUFAF5 variants and optic neuropathy (LHON-like or (Leigh-like presentation). Hence, this gene should be promoted to Green on Optic neuropathy.
Optic neuropathy v6.36 NDUFAF5 Ida Ertmanska Gene: ndufaf5 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.35 NDUFAF5 Ida Ertmanska gene: NDUFAF5 was added
gene: NDUFAF5 was added to Optic neuropathy. Sources: Literature
Q2_26_promote_green tags were added to gene: NDUFAF5.
Mode of inheritance for gene: NDUFAF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFAF5 were set to 21607760; 30473481; 32918965; 36580434
Phenotypes for gene: NDUFAF5 were set to Mitochondrial complex I deficiency, nuclear type 16, OMIM:618238
Review for gene: NDUFAF5 was set to GREEN
Added comment: Saada et al., 2012 PMID: 21607760
P1 - Male, Ashkenazi Jewish ancestry - diagnosed with Leigh syndrome, optic atrophy noted at 26 months. Homozygous for NDUFAF5:c.749G>T, p.Gly250Val.

Simon et al., 2020, PMID: 30473481
P2 - Female, Taiwanese descent - presented at twenty-seven months of age with strabismus, followed by ptosis and vomiting during an intercurrent illness. Ophthalmological testing at 7yrs old revealed nystagmus as well as optic neuritis.

Mansukhani et al. 2021, PMID: 32918965
Proband with LHONplus phenotype, compound het for nonsense & missense variants.

Chen et al. 2024, PMID: 36580434
Proband with LHON-like phenotype with cognitive impairment, hom for frameshift NDUFAF5 variant c.1004_1007del, p.N335Tfs*37 (asymptomatic parents both het).
Sources: Literature
Optic neuropathy v6.34 NDUFB11 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family O - proband with hemizygous NDUFB11 variant c.276_278del p.(F93del) and insidious OA onset at 0-1yrs, optic nerve atrophy seen on MRI, temporal pallor on fundus exam, megaloblastic anaemia, abnormality of the gallbladder, and folate deficiency.

PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

This gene is associated with AR ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family O - proband with hemizygous NDUFB11 variant c.276_278del p.(F93del) and insidious OA onset at 0-1yrs, optic nerve atrophy seen on MRI, temporal pallor on fundus exam, megaloblastic anaemia, abnormality of the gallbladder, and folate deficiency.

PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

This gene is associated with XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 (accessed 26th May 2026).
Optic neuropathy v6.34 NDUFS2 Ida Ertmanska Phenotypes for gene: NDUFS2 were changed from Mitochondrial complex I deficiency, nuclear type 6, 618228 to Mitochondrial complex I deficiency, nuclear type 6, OMIM:618228; ?Leber-like hereditary optic neuropathy, autosomal recessive 2, OMIM:620569
Optic neuropathy v6.33 NDUFS2 Ida Ertmanska Publications for gene: NDUFS2 were set to 28031252
Optic neuropathy v6.32 NDUFS2 Ida Ertmanska Classified gene: NDUFS2 as Amber List (moderate evidence)
Optic neuropathy v6.32 NDUFS2 Ida Ertmanska Added comment: Comment on list classification: There are at least 5 unrelated families with biallelic NDUFS2 variants and optic atrophy (LHON-like or Leigh-like presentation). Hence, this gene should be promoted to Green at the next update.
Optic neuropathy v6.32 NDUFS2 Ida Ertmanska Gene: ndufs2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.31 NDUFS2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFS2.
Optic neuropathy v6.31 NDUFS2 Ida Ertmanska changed review comment from: Loeffen et al. 2001, PMID: 11220739: 3 families with AR NDUFS2-related CI deficiency; in 2 of these families, symptoms included OA.

Gerber et al. 2017, PMID: 28031252: one family with 3 affected siblings with LHON-like phenotype, compound het for missense variants.

Fiorini et al. 2023, PMID: 36913248: listed in table (1 French family), but likely corresponds Gerber et al. 2017.

NDUFS2 is associated with AR Mitochondrial complex I deficiency, nuclear type 6, OMIM:618228 and AR ?Leber-like hereditary optic neuropathy, autosomal recessive 2, OMIM:620569 in OMIM (accessed 27th May 2026).; to: Loeffen et al. 2001, PMID: 11220739: 3 families with AR NDUFS2-related CI deficiency; in 2 of these families, symptoms included OA, third proband died shortly after birth.
Family A: hom c.683G>A, p.Arg228Gln - fine horizontal nystagmus and bilateral OA
Family C: hom c.1237T>C, p.Ser413Pro - horizontal nystagmus, pallor of the optic discs

Tuppen et al., 2010 PMID: 20819849: recurrent p.Met292Th NDUFS2 mutation causes Leigh syndrome in multiple families.
Patient 22 - Female patient with psychomotor delay, learning difficulties and episodes of tonic upward eye deviation were noted from infancy. She subsequently developed progressive dystonia affecting all four limbs, optic nerve hypoplasia, dysarthria and dysphagia.
Patient 35 - Male patient, presented at 34 months of age with developmental delay, ataxia, nystagmus, optic atrophy and a mild, persistent metabolic acidosis (Patient 17 in Salemi R et al).
Caveat: 2 homozygotes reported in gnomAD v4, AF = 0.004563 - VUS in ClinVar.

Gerber et al. 2017, PMID: 28031252: one family with 3 affected siblings with LHON-like phenotype, compound het for missense variants p.Tyr53Cys; p.Tyr308Cys.

NDUFS2 is associated with AR Mitochondrial complex I deficiency, nuclear type 6, OMIM:618228 and AR ?Leber-like hereditary optic neuropathy, autosomal recessive 2, OMIM:620569 in OMIM (accessed 27th May 2026).
Optic neuropathy v6.31 NDUFS2 Ida Ertmanska reviewed gene: NDUFS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11220739, 28031252, 36913248; Phenotypes: Mitochondrial complex I deficiency, nuclear type 6, OMIM:618228, ?Leber-like hereditary optic neuropathy, autosomal recessive 2, OMIM:620569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.31 NSUN3 Ida Ertmanska Phenotypes for gene: NSUN3 were changed from optic neuropathy; optic atrophy; LHON; LHON-like to Combined oxidative phosphorylation deficiency 48, OMIM:619012
Optic neuropathy v6.30 NSUN3 Ida Ertmanska Publications for gene: NSUN3 were set to PMID: 38790159; PMID: 40465263
Optic neuropathy v6.29 NSUN3 Ida Ertmanska Classified gene: NSUN3 as Amber List (moderate evidence)
Optic neuropathy v6.29 NSUN3 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Neringa Jurkute, there are at least 6 unrelated families reported in literature with optic neuropathy (isolated or syndromic) and biallelic NSUN3 variants. Hence, this gene can be promoted to Green on Optic neuropathy at the next update.
Optic neuropathy v6.29 NSUN3 Ida Ertmanska Gene: nsun3 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.28 NSUN3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NSUN3.
Tag Q2_26_NHS_review tag was added to gene: NSUN3.
Optic neuropathy v6.28 NSUN3 Ida Ertmanska reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38790159, 40465263; Phenotypes: Combined oxidative phosphorylation deficiency 48, OMIM:619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.28 NDUFV2 Ida Ertmanska Phenotypes for gene: NDUFV2 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 7, OMIM:618229
Optic neuropathy v6.27 NDUFV2 Ida Ertmanska Publications for gene: NDUFV2 were set to PMID: 41234160
Optic neuropathy v6.26 NDUFV2 Ida Ertmanska Classified gene: NDUFV2 as Red List (low evidence)
Optic neuropathy v6.26 NDUFV2 Ida Ertmanska Gene: ndufv2 has been classified as Red List (Low Evidence).
Optic neuropathy v6.25 NDUFV2 Ida Ertmanska commented on gene: NDUFV2: Comment on list classification: As there is only one proband reported to date with biallelic NDUFV2 variants and isolated optic atrophy, this gene can only be rated Red on this panel.
Optic neuropathy v6.25 NDUFV2 Ida Ertmanska reviewed gene: NDUFV2: Rating: RED; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 7, OMIM:618229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).
Congenital myopathy v7.25 TRIM32 Anna Sarkozy reviewed gene: TRIM32: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.9 TRAPPC2L Anna Sarkozy reviewed gene: TRAPPC2L: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.25 TNPO3 Anna Sarkozy reviewed gene: TNPO3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital muscular dystrophy v7.9 TCAP Anna Sarkozy reviewed gene: TCAP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.25 FOXK2 Anna Sarkozy reviewed gene: FOXK2: Rating: GREEN; Mode of pathogenicity: ; Publications: 40410591; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital myopathy v7.25 PACSIN3 Anna Sarkozy reviewed gene: PACSIN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 38637313; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.25 TUBA4A Anna Sarkozy reviewed gene: TUBA4A: Rating: GREEN; Mode of pathogenicity: ; Publications: 38413182; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 3 unrelated individuals reported in literature with NDUFV1 variants and optic atrophy (isolated or syndromic). Hence, this gene should be promoted to Green at the next GMS update.; to: Comment on list classification: There are at least 3 unrelated individuals reported in literature with biallelic NDUFV1 variants and optic atrophy (isolated or syndromic). Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFV1.
Tag Q2_26_NHS_review tag was added to gene: NDUFV1.
Optic neuropathy v6.25 NDUFV1 Ida Ertmanska Publications for gene: NDUFV1 were set to 41234160
Optic neuropathy v6.24 NDUFV1 Ida Ertmanska Classified gene: NDUFV1 as Amber List (moderate evidence)
Optic neuropathy v6.24 NDUFV1 Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated individuals reported in literature with NDUFV1 variants and optic atrophy (isolated or syndromic). Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.24 NDUFV1 Ida Ertmanska Gene: ndufv1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.23 NDUFV1 Ida Ertmanska edited their review of gene: NDUFV1: Changed rating: GREEN
Optic neuropathy v6.23 NDUFV1 Ida Ertmanska edited their review of gene: NDUFV1: Changed publications to: 29976978, 34807224, 41234160
Optic neuropathy v6.23 NDUFV1 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family F - proband with a homozygous c.1156C>A, p.Arg386Ser variant in NDUFV1 variant and isolated optic atrophy.

PMID: 34807224 Zanette et al., 2021
P2 - at 11 years old, he presented optic atrophy, sensorineural deafness, ptosis, hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis. Homozygous for NDUFV1 c.1268C>T, p.Thr423Met.

PMID: 29976978 Srivastava et al., 2018
Proband 2 - developed normally until the 6 years of age at which time he presented with neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline. Homozygous for c.1156C > T, p.(Arg386Cys).

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225 (accessed 27th May 2026).
Congenital muscular dystrophy v7.8 TRAPPC2L Arina Puzriakova Classified gene: TRAPPC2L as No list
Congenital muscular dystrophy v7.8 TRAPPC2L Arina Puzriakova Gene: trappc2l has been removed from the panel.
Congenital muscular dystrophy v7.7 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Congenital muscular dystrophy. Sources: NHS GMS
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.24 TRIM32 Arina Puzriakova Classified gene: TRIM32 as No list
Congenital myopathy v7.24 TRIM32 Arina Puzriakova Gene: trim32 has been removed from the panel.
Congenital myopathy v7.23 TRIM32 Arina Puzriakova gene: TRIM32 was added
gene: TRIM32 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: TRIM32 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.22 TNPO3 Arina Puzriakova Classified gene: TNPO3 as No list
Congenital myopathy v7.22 TNPO3 Arina Puzriakova Gene: tnpo3 has been removed from the panel.
Congenital myopathy v7.21 TNPO3 Arina Puzriakova gene: TNPO3 was added
gene: TNPO3 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: TNPO3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.20 FOXK2 Arina Puzriakova Classified gene: FOXK2 as No list
Congenital myopathy v7.20 FOXK2 Arina Puzriakova Gene: foxk2 has been removed from the panel.
Congenital myopathy v7.19 FOXK2 Arina Puzriakova gene: FOXK2 was added
gene: FOXK2 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: FOXK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital myopathy v7.18 PACSIN3 Arina Puzriakova Classified gene: PACSIN3 as No list
Congenital myopathy v7.18 PACSIN3 Arina Puzriakova Gene: pacsin3 has been removed from the panel.
Congenital myopathy v7.17 PACSIN3 Arina Puzriakova gene: PACSIN3 was added
gene: PACSIN3 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: PACSIN3 was set to BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.23 NDUFV1 Ida Ertmanska Phenotypes for gene: NDUFV1 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225
Optic neuropathy v6.22 NDUFV1 Ida Ertmanska Publications for gene: NDUFV1 were set to PMID: 41234160
Optic neuropathy v6.21 NDUFV1 Ida Ertmanska Classified gene: NDUFV1 as Amber List (moderate evidence)
Optic neuropathy v6.21 NDUFV1 Ida Ertmanska Gene: ndufv1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.20 NDUFV1 Ida Ertmanska reviewed gene: NDUFV1: Rating: AMBER; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 4, OMIM:618225; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.16 TUBA4A Arina Puzriakova Classified gene: TUBA4A as No list
Congenital myopathy v7.16 TUBA4A Arina Puzriakova Gene: tuba4a has been removed from the panel.
Congenital myopathy v7.15 TUBA4A Arina Puzriakova gene: TUBA4A was added
gene: TUBA4A was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v6.20 NDUFS7 Ida Ertmanska Phenotypes for gene: NDUFS7 were changed from Optic neuropathy; optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 3, OMIM:618224
Optic neuropathy v6.19 NDUFS7 Ida Ertmanska Publications for gene: NDUFS7 were set to PMID: 41234160
Optic neuropathy v6.18 NDUFS7 Ida Ertmanska Classified gene: NDUFS7 as Amber List (moderate evidence)
Optic neuropathy v6.18 NDUFS7 Ida Ertmanska Added comment: Comment on list classification: There are now 5 unrelated probands reported in literature with biallelic NDUFS7 variants and optic atrophy (isolated or syndromic). Hence, this gene should be promoted to Green on Optic neuropathy at the next update.
Optic neuropathy v6.18 NDUFS7 Ida Ertmanska Gene: ndufs7 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.17 NDUFS7 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFS7.
Tag Q2_26_NHS_review tag was added to gene: NDUFS7.
Optic neuropathy v6.17 NDUFS7 Ida Ertmanska reviewed gene: NDUFS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 3, OMIM:618224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.17 NDUFB11 Ida Ertmanska Phenotypes for gene: NDUFB11 were changed from Optic neuropathy, optic atrophy; LHON-like to ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021
Optic neuropathy v6.16 NDUFB11 Ida Ertmanska Publications for gene: NDUFB11 were set to PMID: 41234160
Optic neuropathy v6.15 NDUFB11 Ida Ertmanska Classified gene: NDUFB11 as Amber List (moderate evidence)
Optic neuropathy v6.15 NDUFB11 Ida Ertmanska Added comment: Comment on list classification: There are now 3 male individuals from 2 families reported with hemizygous NDUFB11 variants and optic atrophy. Hence, this gene can only be rated Amber with the current evidence.
Optic neuropathy v6.15 NDUFB11 Ida Ertmanska Gene: ndufb11 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.14 NDUFB11 Ida Ertmanska edited their review of gene: NDUFB11: Changed publications to: 27488349, 41234160
Optic neuropathy v6.14 NDUFB11 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family O - proband with hemizygous NDUFB11 variant c.276_278del p.(F93del) and insidious OA onset at 0-1yrs, optic nerve atrophy seen on MRI, temporal pallor on fundus exam, megaloblastic anaemia, abnormality of the gallbladder, and folate deficiency.

This gene is associated with AR ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family O - proband with hemizygous NDUFB11 variant c.276_278del p.(F93del) and insidious OA onset at 0-1yrs, optic nerve atrophy seen on MRI, temporal pallor on fundus exam, megaloblastic anaemia, abnormality of the gallbladder, and folate deficiency.

PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

This gene is associated with AR ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 (accessed 26th May 2026).
Rare anaemia v4.6 NDUFB11 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 27th May 2026.
Rare anaemia v4.6 NDUFB11 Ida Ertmanska Phenotypes for gene: NDUFB11 were changed from sideroblastic anaemia to ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021; Linear skin defects with multiple congenital anomalies 3, OMIM:300952; sideroblastic anemia, MONDO:0015194
Rare anaemia v4.5 NDUFB11 Ida Ertmanska Publications for gene: NDUFB11 were set to 27488349
Rare anaemia v4.4 NDUFB11 Ida Ertmanska commented on gene: NDUFB11: Comment on list classification: There are 4 unrelated male probands reported with a recurrent hemizygous p.Phe93del variant in NDUFB11 and sideroblastic anemia. In addition, 2 unrelated male probands have been reported with mild microcytic / normocytic anemia with different NDUFB11 missense variants. The female heterozygous carriers were unaffected. Hence, this gene should be promoted to Green for Rare anaemia, with MOI set to X-LINKED: hemizygous mutation in males, biallelic mutations in females.
Rare anaemia v4.4 NDUFB11 Ida Ertmanska changed review comment from: PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

PMID: 30423443 Reinson et al., 2019
Report of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286C>T and c.328C>T) in NDUFB11.
P2 had persistent mild leukopenia and microcytic anemia, P1 had transient normocytic anemia at 2 months, which he recovered from after iron administration.

This gene is linked to XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 and XLD Linear skin defects with multiple congenital anomalies 3, OMIM:300952 (accessed 27th May 2026).; to: PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

PMID: 30423443 Reinson et al., 2019
Report of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286T>C, p.(Ser96Pro) and c.328C>T, p.Pro110Ser) in NDUFB11.
P2 had persistent mild leukopenia and microcytic anemia, P1 had transient normocytic anemia at 2 months, which he recovered from after iron administration.

This gene is linked to XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 and XLD Linear skin defects with multiple congenital anomalies 3, OMIM:300952 (accessed 27th May 2026).
Rare anaemia v4.4 NDUFB11 Ida Ertmanska edited their review of gene: NDUFB11: Changed phenotypes to: ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021, Linear skin defects with multiple congenital anomalies 3, OMIM:300952, sideroblastic anemia, MONDO:0015194
Rare anaemia v4.4 NDUFB11 Ida Ertmanska edited their review of gene: NDUFB11: Changed publications to: 27488349, 30423443
Rare anaemia v4.4 NDUFB11 Ida Ertmanska changed review comment from: PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

This gene is linked to XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 and XLD Linear skin defects with multiple congenital anomalies 3, OMIM:300952 (accessed 27th May 2026).; to: PMID: 27488349 Lichtenstein et al., 2016
Report of 5 males from 4 families with hemizygous NDUFB11 c.276_278del, p.F93del variant and congenital sideroblastic anemia. Method: WES. Heterozygous females were unaffected, X-inactivation skewing. Recurrent variant, confirmed de novo in one proband, and another proband's mother - posed to occur due to polymerase slipping. Variable syndromic features seen in addition to anemia: short stature (2 families), optic atrophy + DD (1 family), myopathy (2 families), lactic acidosis (1 individual); epilepsy, single kidney, pulmonary stenosis, congenital inguinal hernia (1 individual).

PMID: 30423443 Reinson et al., 2019
Report of two male patients with lactic acidosis, hypertrophic cardiomyopathy and isolated complex I deficiency due to de novo hemizygous mutations (c.286C>T and c.328C>T) in NDUFB11.
P2 had persistent mild leukopenia and microcytic anemia, P1 had transient normocytic anemia at 2 months, which he recovered from after iron administration.

This gene is linked to XL ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021 and XLD Linear skin defects with multiple congenital anomalies 3, OMIM:300952 (accessed 27th May 2026).
Rare anaemia v4.4 NDUFB11 Ida Ertmanska Publications for gene: NDUFB11 were set to
Rare anaemia v4.3 NDUFB11 Ida Ertmanska Mode of inheritance for gene: NDUFB11 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare anaemia v4.2 NDUFB11 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFB11.
Rare anaemia v4.2 NDUFB11 Ida Ertmanska reviewed gene: NDUFB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 27488349; Phenotypes: ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021, Linear skin defects with multiple congenital anomalies 3, OMIM:300952; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pigmentary skin disorders v5.2 NDUFB11 Ida Ertmanska reviewed gene: NDUFB11: Rating: AMBER; Mode of pathogenicity: None; Publications: 27488349, 41234160; Phenotypes: ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Optic neuropathy v6.14 NDUFAF8 Ida Ertmanska changed review comment from: Comment on list classification: There are at least 6 individuals from 3 unrelated individuals reported in literature with biallelic NDUFAF8 variants and optic atrophy - isolated or syndromic. Hence, this gene should be promoted to Green at the next GMS update.; to: Comment on list classification: There are at least 6 individuals from 3 unrelated families reported in literature with biallelic NDUFAF8 variants and optic atrophy - isolated or syndromic. Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.14 NDUFAF8 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

5/6 patients reported with NDUFAF8 variants had isolated optic atrophy; the sixth proband had OA plus nystagmus and cerebellar ataxia.
Family U - 2 sibs hom for c.44T>G p.(L15R) - isolated OA, MRI normal
Families W & V (4 individuals from 2 families)- hom for c.195+271C>T p.? deep intronic variant - insidious isolated OA in family W, individuals in Family V had LHON-like presentation of OA + strabismus, hyperopia, non-specific white matter lesions on MRI (3/3), also mild DD, nystagmus, and unsteady gate in 1/3.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

5/6 patients reported with NDUFAF8 variants had isolated optic atrophy; the sixth proband had OA plus nystagmus and cerebellar ataxia.
Family U - 2 sibs hom for c.44T>G p.(L15R) - isolated OA, MRI normal
Families W & V (4 individuals from 2 families)- hom for c.195+271C>T p.? deep intronic variant - insidious isolated OA in family W, individuals in Family V had LHON-like presentation of OA + strabismus, hyperopia, non-specific white matter lesions on MRI (3/3), also mild DD, nystagmus, and unsteady gate in 1/3.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776 (accessed 26th May 2026).
Optic neuropathy v6.14 NDUFAF4 Ida Ertmanska Tag Q2_26_NHS_review tag was added to gene: NDUFAF4.
Optic neuropathy v6.14 NDUFAF8 Achchuthan Shanmugasundram Tag Q2_26_NHS_review tag was added to gene: NDUFAF8.
Optic neuropathy v6.14 NDUFB11 Ida Ertmanska reviewed gene: NDUFB11: Rating: AMBER; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: ?Mitochondrial complex I deficiency, nuclear type 30, OMIM:301021; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Optic neuropathy v6.14 NDUFAF8 Ida Ertmanska Phenotypes for gene: NDUFAF8 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776
Optic neuropathy v6.13 NDUFAF8 Ida Ertmanska Publications for gene: NDUFAF8 were set to PMID: 41234160
Optic neuropathy v6.12 NDUFAF8 Ida Ertmanska Classified gene: NDUFAF8 as Amber List (moderate evidence)
Optic neuropathy v6.12 NDUFAF8 Ida Ertmanska Added comment: Comment on list classification: There are at least 6 individuals from 3 unrelated individuals reported in literature with biallelic NDUFAF8 variants and optic atrophy - isolated or syndromic. Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.12 NDUFAF8 Ida Ertmanska Gene: ndufaf8 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.11 NDUFAF8 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFAF8.
Optic neuropathy v6.11 NDUFAF8 Ida Ertmanska reviewed gene: NDUFAF8: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.11 NDUFAF4 Ida Ertmanska Phenotypes for gene: NDUFAF4 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237
Optic neuropathy v6.10 NDUFAF4 Ida Ertmanska Publications for gene: NDUFAF4 were set to PMID: 41234160
Optic neuropathy v6.9 NDUFAF4 Ida Ertmanska Classified gene: NDUFAF4 as Amber List (moderate evidence)
Optic neuropathy v6.9 NDUFAF4 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic NDUFAF4 variants and isolated optic atrophy. Hence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.9 NDUFAF4 Ida Ertmanska Gene: ndufaf4 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.8 NDUFAF4 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFAF4.
Optic neuropathy v6.8 NDUFAF4 Ida Ertmanska edited their review of gene: NDUFAF4: Changed publications to: 38381526, 41234160
Optic neuropathy v6.8 NDUFAF4 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

2 unrelated probands carried NDUFAF4 variants:
Family S - proband with NDUFAF4 comp het variants c.224del p.(P75Lfs*7) and c.413T>C p.(I138T), with isolated optic atrophy
Family T - 2 sibs homozygous for c.413T>C p.(I138T) variant in NDUFAF4 with isolated optic atrophy

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

2 unrelated probands carried NDUFAF4 variants:
Family S - proband with NDUFAF4 comp het variants c.224del p.(P75Lfs*7) and c.413T>C p.(I138T), with isolated optic atrophy
Family T - 2 sibs homozygous for c.413T>C p.(I138T) variant in NDUFAF4 with isolated optic atrophy

PMID: 38381526 Barboni et al., 2025
Report of a 17yo boy with subacute bilateral visual loss with no pain - atypical LHON diagnosis. He was comp het for NDUFAF4: c.413T>C, p.Ile138Thr and c.224del, p.Pro75LeufsTer7. Temporal pallor of both the optic discs, optic disc microangiopathy, and temporal retinal nerve fiber layer (RNFL) thinning noted at 12 yrs old.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237 (accessed 26th May 2026).
Optic neuropathy v6.8 NDUFAF4 Ida Ertmanska reviewed gene: NDUFAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 15, OMIM:618237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.8 NDUFAF3 Ida Ertmanska Phenotypes for gene: NDUFAF3 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 18, OMIM:618240
Optic neuropathy v6.7 NDUFAF3 Ida Ertmanska Publications for gene: NDUFAF3 were set to PMID: 41234160
Optic neuropathy v6.6 NDUFAF3 Ida Ertmanska Classified gene: NDUFAF3 as Amber List (moderate evidence)
Optic neuropathy v6.6 NDUFAF3 Ida Ertmanska Added comment: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic NDUFAF3 variants and Leigh syndrome spectrum, including optic atrophy. An additional case was reported with neonatal mitochondrial disease and pallor of the optic disc, with another homozygous NDUFAF3 variants. Based on available evidence, this gene should remain Amber on optic neuropathy, until more evidence emerges.
Optic neuropathy v6.6 NDUFAF3 Ida Ertmanska Gene: ndufaf3 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.5 NDUFAF3 Ida Ertmanska edited their review of gene: NDUFAF3: Changed publications to: 19463981, 27986404, 41234160
Optic neuropathy v6.5 NDUFAF3 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family R - proband with LSS, presented with Motor delay, Abnormal basal ganglia MRI signal intensity, optic atrophy with insidious onset at 0-3 years of age; harboured NDUFAF3 c.5C>A, p.(A2D) and c.489_490del, p.(G164Sfs*29) comp het variants

PMID: 27986404 Baertling et al., 2017
Female Indian patient with Leigh syndrome diagnosis, bilateral optic atrophy was noted at 15 months. WES revealed a homozygous NDUFAF3 variant c.494C>T, p.Ala165Val.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 18, OMIM:618240 (accessed 26th May 2026).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

Family R - proband with LSS, presented with Motor delay, Abnormal basal ganglia MRI signal intensity, optic atrophy with insidious onset at 0-3 years of age; harboured NDUFAF3 c.5C>A, p.(A2D) and c.489_490del, p.(G164Sfs*29) comp het variants

PMID: 27986404 Baertling et al., 2017
Female Indian patient with Leigh syndrome diagnosis, bilateral optic atrophy was noted at 15 months. WES revealed a homozygous NDUFAF3 variant c.494C>T, p.Ala165Val.

PMID: 19463981 Saada et al. 2009
Male proband II-1 of Arab descent with neonatal mitochondrial disease diagnosis, including bilateral pallor of the optic disc seen on fundoscopy (no MRI done). He was homozygous for c.365G>C, p. R122P in NDUFAF3.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 18, OMIM:618240 (accessed 26th May 2026).
Optic neuropathy v6.5 NDUFAF3 Ida Ertmanska reviewed gene: NDUFAF3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27986404, 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 18, OMIM:618240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v6.5 NDUFAF2 Ida Ertmanska changed review comment from: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

2 unrelated probands carried NDUFAF2 variants:
Two sibs from family P - carrying variants in NDUFAF2: c.95A>G p.(Y32C) and c.148del p.(R50Efs*3), showed OA and peripheral axonal neuropathy - "OA-Plus"
Proband from family Q - homozygous for NDUFAF2 c.114C>G, p.(Y38*), showed OA and peripheral axonal neuropathy - "OA-Plus"

PMID: 37938061 Chen et al., 2024
Report of a 35yo patient with AR LHON - isolated optic atrophy, no Leigh-like encephalopathy. He reported vision problems starting at age 15yrs. Brain MRI showed bilateral thin optic nerve. WES detected comp het variants in NDUFAF2: c.139C>T, p.Arg47*, and c.148del, p.Arg50Glufs*3 - confirmed in trans.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233 (accessed 26th May 2025).; to: PMID: 41234160 Fiorini et al., 2025
Authors identified candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear Complex I related genes.

2 unrelated probands carried NDUFAF2 variants:
Two sibs from family P - carrying variants in NDUFAF2: c.95A>G p.(Y32C) and c.148del p.(R50Efs*3), showed OA and peripheral axonal neuropathy - "OA-Plus"
Proband from family Q - homozygous for NDUFAF2 c.114C>G, p.(Y38*), showed OA and peripheral axonal neuropathy - "OA-Plus"

PMID: 37938061 Chen et al., 2024
Report of a 35yo patient with AR LHON - isolated optic atrophy, no Leigh-like encephalopathy. He reported vision problems starting at age 15yrs. Brain MRI showed bilateral thin optic nerve. WES detected comp het variants in NDUFAF2: c.139C>T, p.Arg47*, and c.148del, p.Arg50Glufs*3 - confirmed in trans.

This gene is associated with AR Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233 (accessed 26th May 2026).
Optic neuropathy v6.5 NDUFAF2 Ida Ertmanska Classified gene: NDUFAF2 as Amber List (moderate evidence)
Optic neuropathy v6.5 NDUFAF2 Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated cases reported in literature with biallelic NDUFAF2 variants and optic neuropathy (either isolated OA or syndromic). Based on available evidence, this gene should be promoted to Green at the next GMS update.
Optic neuropathy v6.5 NDUFAF2 Ida Ertmanska Gene: ndufaf2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v6.4 NDUFAF2 Ida Ertmanska Phenotypes for gene: NDUFAF2 were changed from Optic neuropathy, optic atrophy; LHON-like to Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233
Optic neuropathy v6.3 NDUFAF2 Ida Ertmanska Publications for gene: NDUFAF2 were set to PMID: 41234160
Optic neuropathy v6.2 NDUFAF2 Ida Ertmanska Tag Q2_26_NHS_review tag was added to gene: NDUFAF2.
Optic neuropathy v6.2 NDUFAF2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: NDUFAF2.
Optic neuropathy v6.2 NDUFAF2 Ida Ertmanska reviewed gene: NDUFAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37938061, 41234160; Phenotypes: Mitochondrial complex I deficiency, nuclear type 10, OMIM:618233; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v9.8 SHROOM4 Ida Ertmanska Tag watchlist tag was added to gene: SHROOM4.
Early onset or syndromic epilepsy v9.8 SHROOM4 Ida Ertmanska commented on gene: SHROOM4: Comment on list classification: While there are 6 cases with seizures reported in literature, it is from a single publication and two of the variants are present in hemizygous state in GnomAD. There are several other SHROOM4 gene-phenotype associations reported with limited case numbers. Hence, on advice of Genomics England's Clinical Team, this gene should be rated Amber with a 'watchlist' tag, until more evidence emerges.
Limb disorders v8.7 IFT57 Ida Ertmanska Publications for gene: IFT57 were set to 27060890; 40273360
Limb disorders v8.6 IFT57 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: IFT57.
Limb disorders v8.6 IFT57 Ida Ertmanska commented on gene: IFT57: Comment on list classification: There are 2 unrelated individuals reported in literature with bialellic IFT57 variants and polydactyly. Functional evidence from a knockout mouse model supports this gene-phenotype association. Hence, this gene should be promoted to Green on Limb disorders at the next update.
Limb disorders v8.6 IFT57 Ida Ertmanska edited their review of gene: IFT57: Changed publications to: 17027958, 27060890, 40273360
Limb disorders v8.6 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia, polydactyly, and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia, polydactyly, and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

PMID: 17027958 Houde et al., 2006
IFT57-/- knockout mouse (old gene name Hippi) only survived roughly until E9.5. One embryo survived until E13.5, and showed exencephaly, hypotelorism, and polydactyly on both fore and hind limbs.

Sources: Literature
Limb disorders v8.6 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia, polydactyly, and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature
Monogenic hearing loss v6.15 DSPP Ida Ertmanska commented on gene: DSPP: Comment on list classification: There is limited and conflicting evidence regarding the association between DSPP variants and dominant hearing loss. There are 3 Chinese families reported with DSPP missense variants and hearing loss, including one pedigree with a common likely benign variant. The other two families had both dentinogenesis imperfecta and hearing loss, and harboured the same DSPP variant detected by linkage analysis/targeted DSPP seq - another gene likely responsible for hearing loss. In addition, numerous other cases with 59+ different DSPP variants have been reported in literature with isolated dentinogenesis imperfecta.
Monogenic hearing loss v6.15 DSPP Ida Ertmanska Phenotypes for gene: DSPP were changed from Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594; Dentin dysplasia, type II, OMIM:125420; Dentinogenesis imperfecta, Shields type II, OMIM:125490; Dentinogenesis imperfecta, Shields type III, OMIM:125500 to Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594; Dentin dysplasia, type II, OMIM:125420; Dentinogenesis imperfecta, Shields type II, OMIM:125490; Dentinogenesis imperfecta, Shields type III, OMIM:125500
Monogenic hearing loss v6.15 DSPP Ida Ertmanska Phenotypes for gene: DSPP were changed from hearing loss; Dentinogenesis imperfecta, Shields type II, 125490; Deafness, autosomal dominant 36, with dentinogenesis, 605594; Dentinogenesis imperfecta, Shields type III, 125500; Dentin dysplasia, type II, 125420; Dentin dysplasia, type II,1254203 to Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594; Dentin dysplasia, type II, OMIM:125420; Dentinogenesis imperfecta, Shields type II, OMIM:125490; Dentinogenesis imperfecta, Shields type III, OMIM:125500
Monogenic hearing loss v6.14 DSPP Ida Ertmanska Publications for gene: DSPP were set to PMID:10706475; 11116156; 11175770; 11175779; 11175790; 12354781; 12721295; 14758537; 15592686; 15954904; 17210923; 18456718; 22392858; 22582013; 2433419; 2462619; 7573043; 8995371; 9533027
Monogenic hearing loss v6.13 DSPP Ida Ertmanska Tag Q2_26_demote_red tag was added to gene: DSPP.
Monogenic hearing loss v6.13 DSPP Ida Ertmanska edited their review of gene: DSPP: Changed publications to: 11175790, 17686168, 29741433, 33229591, 39806231
Monogenic hearing loss v6.13 DSPP Ida Ertmanska changed review comment from: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li ey al., 2018
Proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).; to: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li et al., 2018
Chinese proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).
Monogenic hearing loss v6.13 DSPP Ida Ertmanska changed review comment from: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI).

Hearing loss has not been reported in any other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025); to: PMID: 11175790 Xiao et al., 2001
2 Chinese families with sensorineural hearing loss and dentinogenesis imperfecta (DI), both het for DSPP variant c.49C>A (p.Pro17Thr). Method: linkage analysis, followed by DSPP sequencing.

PMID: 17686168
Chinese family with DI and the same DSPP residue mutated as in PMID: 11175790 (c.49C>T, p.Pro17Ser), and no hearing loss.

PMID: 29741433 Li ey al., 2018
Proband with Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II, harboured DSPP c.3085A>G, p.Asn1029Asp and c.3087C>T, p.Asn1029= variants in cis. Method: WGS of proband and 7 family members. 3 affected individuals: father and his two male sons (twins), all with the same DSPP allele.
Both DSPP variants have high gnomAD frequencies in East Asian population (0.01039 and 0.009011), with homozygous individuals also reported; p.Asn1029Asp is Likely Benign in ClinVar - unlikely to be causal.

PMID: 33229591 Boucher et al., 2020
Age-related hearing loss cohort. Patient 6708 - harboured a c.776C > T; p.(Ser259Phe) variant in DSPP.

Hearing loss has not been mentioned as a feature in numerous other cases with DSPP variants and DI (59 variants reported in literature according to PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025).
Amelogenesis imperfecta v4.33 DSPP Ida Ertmanska edited their review of gene: DSPP: Changed publications to: 18456718, 39806231
Amelogenesis imperfecta v4.33 DSPP Ida Ertmanska Classified gene: DSPP as Amber List (moderate evidence)
Amelogenesis imperfecta v4.33 DSPP Ida Ertmanska Gene: dspp has been classified as Amber List (Moderate Evidence).
Amelogenesis imperfecta v4.32 DSPP Ida Ertmanska Publications for gene: DSPP were set to 1845671839806231
Amelogenesis imperfecta v4.31 DSPP Ida Ertmanska gene: DSPP was added
gene: DSPP was added to Amelogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: DSPP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DSPP were set to 1845671839806231
Phenotypes for gene: DSPP were set to Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594; Dentin dysplasia, type II, OMIM:125420; Dentinogenesis imperfecta, Shields type II, OMIM:125490; Dentinogenesis imperfecta, Shields type III, OMIM:125500
Review for gene: DSPP was set to GREEN
Added comment: PMID: 39806231 Gilani, Saikia, and Anthonappa, 2025
Lit review of 322 cases with non-syndromic dentinogenesis imperfecta (DI - characterized clinically by amber or gray-yellow opalescent tooth discoloration, obliteration of pulp chambers and root canals, and attrition. Both deciduous and permanent teeth are affected (PMID: 18456718 Song et al., 2008).
DSPP mutations were the most frequent, with with 59 documented variants from 37 publications. 34/59 variants were in exon 5 of DSPP.
Sources: Literature
Monogenic hearing loss v6.13 DSPP Ida Ertmanska reviewed gene: DSPP: Rating: RED; Mode of pathogenicity: None; Publications: 11175790, 39806231; Phenotypes: Deafness, autosomal dominant 39, with dentinogenesis, OMIM:605594, Dentin dysplasia, type II, OMIM:125420, Dentinogenesis imperfecta, Shields type II, OMIM:125490, Dentinogenesis imperfecta, Shields type III, OMIM:125500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic hearing loss v6.13 PLCG1 Ida Ertmanska commented on gene: PLCG1: Comment on list classification: There are now 3 unrelated individuals with heterozygous PLCG1 variants and hearing loss. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v10.18 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Intellectual disability v10.17 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Intellectual disability v10.17 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and ID/DD. Hence, this gene should be promoted to Green at the next update.; Changed publications to: 27435318, 40385417, 40621786, 42012897
Intellectual disability v10.17 BORCS5 Ida Ertmanska commented on gene: BORCS5: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."
Childhood onset hereditary spastic paraplegia v9.2 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Childhood onset hereditary spastic paraplegia v9.1 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Childhood onset hereditary spastic paraplegia v9.1 BORCS5 Ida Ertmanska commented on gene: BORCS5: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and childhood-onset HSP. Hence, this gene should be promoted to Green at the next update.
Childhood onset hereditary spastic paraplegia v9.1 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."; Changed publications to: 27435318, 40385417, 40621786, 42012897
Optic neuropathy v6.2 BORCS5 Ida Ertmanska commented on gene: BORCS5: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and optic neuropathy. Hence, this gene should be promoted to Green at the next update.
Optic neuropathy v6.2 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."; Changed publications to: 27435318, 40385417, 40621786, 42012897
Optic neuropathy v6.2 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Early onset or syndromic epilepsy v9.8 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Optic neuropathy v6.1 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Arthrogryposis v10.6 BORCS5 Ida Ertmanska Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Arthrogryposis v10.5 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Arthrogryposis v10.5 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and lethal arthrogryposis. Hence, this gene should be promoted to Green at the next update.; Changed publications to: 27435318, 40385417, 40621786, 42012897
Arthrogryposis v10.5 BORCS5 Ida Ertmanska commented on gene: BORCS5: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."
Early onset or syndromic epilepsy v9.7 BORCS5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BORCS5.
Early onset or syndromic epilepsy v9.7 BORCS5 Ida Ertmanska commented on gene: BORCS5: Comment on list classification: There are now more than 3 published unrelated cases with biallelic BORCS5 variants and epilepsy. Hence, this gene should be promoted to Green at the next update.
Early onset or syndromic epilepsy v9.7 BORCS5 Ida Ertmanska edited their review of gene: BORCS5: Added comment: PMID: 42012897 Mencacci et al. - now published (April 2026)
Final version of the article describes 16 individuals from 9 families with biallelic BORCS5 variants.
"Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, as well as progressive global cerebral atrophy, consistent with neurodegeneration."; Changed publications to: 27435318, 40385417, 40621786, 42012897
Structural eye disease v5.6 FBN1 Ida Ertmanska Publications for gene: FBN1 were set to 1301946, 8136837
Structural eye disease v5.5 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Structural eye disease v5.5 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Ectopia lentis (displacement or malposition of the eye’s natural lens) is a very common feature in individuals with Marfan Syndrome. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Structural eye disease v5.5 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Pneumothorax - familial v3.6 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Ehlers Danlos syndrome with a likely monogenic cause v4.11 FBN1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Thoracic aortic aneurysm or dissection (GMS) should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Ehlers Danlos syndrome with a likely monogenic cause should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Pneumothorax - familial v3.6 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. As stated by previous reviewers, pneumothorax is a common feature of Marfan Syndrome. Hence, the MOI on Pneumothorax - familial should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Pneumothorax - familial v3.6 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v4.11 FBN1 Ida Ertmanska Phenotypes for gene: FBN1 were changed from Marfan syndrome, OMIM:154700 to Marfan syndrome, OMIM:154700; Marfan syndrome, MONDO:0007947
Ehlers Danlos syndrome with a likely monogenic cause v4.10 FBN1 Ida Ertmanska Publications for gene: FBN1 were set to
Ehlers Danlos syndrome with a likely monogenic cause v4.9 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Ehlers Danlos syndrome with a likely monogenic cause v4.9 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Thoracic aortic aneurysm or dissection (GMS) should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Ehlers Danlos syndrome with a likely monogenic cause v4.9 FBN1 Ida Ertmanska edited their review of gene: FBN1: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v4.9 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v5.4 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Thoracic aortic aneurysm or dissection (GMS) should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Thoracic aortic aneurysm or dissection (GMS) v5.4 FBN1 Ida Ertmanska Publications for gene: FBN1 were set to 26888179; 20082464; 7762551
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska changed review comment from: PMID: 23278365 Hogue et al., 2013
Report of a proband (Mexican-American woman, consanguineous parents) + literature review of 4 additional unrelated families with biallelic FBN1 variants and severe Marfan syndrome - heterozygous parents were either asymptomatic or had a milder form of Marfan syndrome. Mostly biallelic missense, one instance of missense + deletion in 2 sibs. Proband presented with scoliosis, arachnodactyly, dislocated lenses, mitral valve prolapse, aortic dilatation, dural ectasias.

PMID: 27582083 Arnaud et al., 2017
In a large cohort of Marfan syndrome patients, 4 probands were homozygous and 22 potentially comp het for FBN1 variants (5 confirmed to be in trans). All 4 homozygous individuals harboured missense variants; comp het cases either had biallelic missense FBN1 variants, or missense + nonsense. Heterozygous carriers usually also diagnosed with MFS, sometimes very mild e.g., isolated mild skeletal features in women. The severity of symptoms and age of onset varied a lot, both between biallelic and among monoallelic cases.

PMID: 31950671 McInerney-Leo et al., 2020
Report of a pedigree with Marfan syndrome (ectopia lentis, though the skeletal phenotype is variable, and not all have aortic dilatation) - some individuals with monoallelic and some with biallelic FBN1 variants.
All subjects with Marfan syndrome harboured p.Tyr754Cys in FBN1. An additional variant (p.Met2273Thr), previously associated with 'incomplete' MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years.
The heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair.; to: PMID: 23278365 Hogue et al., 2013
Report of a proband (Mexican-American woman, consanguineous parents) + literature review of 4 additional unrelated families with biallelic FBN1 variants and severe Marfan syndrome - heterozygous parents were either asymptomatic or had a milder form of Marfan syndrome. Mostly biallelic missense, one instance of missense + deletion in 2 sibs. Proband presented with scoliosis, arachnodactyly, dislocated lenses, mitral valve prolapse, aortic dilatation, dural ectasias.

PMID: 27582083 Arnaud et al., 2017
In a large cohort of Marfan syndrome patients, 4 probands were homozygous and 22 potentially comp het for FBN1 variants (5 confirmed to be in trans). All 4 homozygous individuals harboured missense variants; comp het cases either had biallelic missense FBN1 variants, or missense + nonsense. Heterozygous carriers usually also diagnosed with MFS, sometimes very mild e.g., isolated mild skeletal features in women. The severity of symptoms and age of onset varied a lot, both between biallelic and among monoallelic cases.

PMID: 31950671 McInerney-Leo et al., 2020
Report of a pedigree with Marfan syndrome (ectopia lentis, though the skeletal phenotype is variable, and not all have aortic dilatation) - some individuals with monoallelic and some with biallelic FBN1 variants.
All subjects with Marfan syndrome harboured p.Tyr754Cys in FBN1. An additional variant (p.Met2273Thr), previously associated with 'incomplete' MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years.
The heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair.

The association between FBN1 and Marfan syndrome is rated as Definitive in Gene2Phenotype, both for the AD and AR inheritance patterns.
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital myopathy v7.14 DST Anna Sarkozy reviewed gene: DST: Rating: GREEN; Mode of pathogenicity: ; Publications: 40497796; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.6 HMGCR Anna Sarkozy reviewed gene: HMGCR: Rating: GREEN; Mode of pathogenicity: ; Publications: 37167966, 36745799; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 CASQ1 Anna Sarkozy edited their review of gene: CASQ1: Added comment: vacuolar myopathy with aggregates, in absence of biopsy this condition could be in strong differential with CM; Changed publications to: 26136523, PMID: 30258016, 25116801
Congenital myopathy v7.14 SPTAN1 Anna Sarkozy reviewed gene: SPTAN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 40999194, 40023774; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.14 SPTBN4 Anna Sarkozy reviewed gene: SPTBN4: Rating: GREEN; Mode of pathogenicity: ; Publications: 33772159, 28540413; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.6 TK2 Anna Sarkozy reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 TK2 Anna Sarkozy reviewed gene: TK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.6 MCOLN1 Anna Sarkozy reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 33454187; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 MCOLN1 Anna Sarkozy reviewed gene: MCOLN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 33454187; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 JPH1 Anna Sarkozy reviewed gene: JPH1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39209426; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 HRAS Anna Sarkozy edited their review of gene: HRAS: Added comment: congenital myopathy with excess muscle spindles; congenital weakness, hypotonia, arthrogryposis, atrial tachycardia, hypertrophic cardiomyopathy, and marked excess of muscle spindles on biopsy.; Changed rating: GREEN; Changed publications to: 17412879, 11150980; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.14 HNRNPA1 Anna Sarkozy edited their review of gene: HNRNPA1: Added comment: amber in distal myopathy , green in ALS panel, now reported in families with childhood onset myopathy; Changed rating: GREEN; Changed publications to: 39121134; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.14 HMGCS1 Anna Sarkozy reviewed gene: HMGCS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 39531736; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.14 CNTN1 Anna Sarkozy edited their review of gene: CNTN1: Added comment: 2 families reported with variants in this gene; severe phenotype with fetal akinesia and nonspecific myopathic features on skeletal muscle biopsy.; Changed rating: GREEN; Changed publications to: 32779773, 19026398
Congenital myopathy v7.14 CCDC78 Anna Sarkozy edited their review of gene: CCDC78: Added comment: 2 families reported. Recent paper supporting functional role; Changed publications to: 22818856, 39273074; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.14 CACNA1H Anna Sarkozy reviewed gene: CACNA1H: Rating: GREEN; Mode of pathogenicity: ; Publications: 31070086; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.5 HMGCR Arina Puzriakova Classified gene: HMGCR as No list
Congenital muscular dystrophy v7.5 HMGCR Arina Puzriakova Gene: hmgcr has been removed from the panel.
Congenital muscular dystrophy v7.4 HMGCR Arina Puzriakova gene: HMGCR was added
gene: HMGCR was added to Congenital muscular dystrophy. Sources: NHS GMS
Mode of inheritance for gene: HMGCR was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.13 SPTAN1 Arina Puzriakova Classified gene: SPTAN1 as No list
Congenital myopathy v7.13 SPTAN1 Arina Puzriakova Gene: sptan1 has been removed from the panel.
Adult onset neurodegenerative disorder v9.1 LRSAM1 Oliver Ziff gene: LRSAM1 was added
gene: LRSAM1 was added to Adult onset neurodegenerative disorder. Sources: Literature,Expert Review
Mode of inheritance for gene: LRSAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRSAM1 were set to 22781092; 28335037
Phenotypes for gene: LRSAM1 were set to Charcot Marie Toothe disease, axonal, type 2P, 614436
Penetrance for gene: LRSAM1 were set to Complete
Mode of pathogenicity for gene: LRSAM1 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: LRSAM1 was set to GREEN
gene: LRSAM1 was marked as current diagnostic
Added comment: Causes CMT2P with marked motor features out of proportion to sensory loss, presenting as an PMA mimic. Needs inclusion in R460.1 to avoid R78 reanalysis.
Sources: Literature, Expert Review
Congenital myopathy v7.12 SPTAN1 Arina Puzriakova gene: SPTAN1 was added
gene: SPTAN1 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v7.11 TK2 Arina Puzriakova Classified gene: TK2 as No list
Congenital myopathy v7.11 TK2 Arina Puzriakova Gene: tk2 has been removed from the panel.
Congenital myopathy v7.10 TK2 Arina Puzriakova gene: TK2 was added
gene: TK2 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: TK2 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v7.3 MCOLN1 Arina Puzriakova Classified gene: MCOLN1 as No list
Congenital muscular dystrophy v7.3 MCOLN1 Arina Puzriakova Gene: mcoln1 has been removed from the panel.
Congenital myopathy v7.9 MCOLN1 Arina Puzriakova Classified gene: MCOLN1 as No list
Congenital myopathy v7.9 MCOLN1 Arina Puzriakova Gene: mcoln1 has been removed from the panel.
Adult onset neurodegenerative disorder v9.1 MORC2 Oliver Ziff gene: MORC2 was added
gene: MORC2 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: MORC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MORC2 were set to 26497905; 26659848
Phenotypes for gene: MORC2 were set to Charcot-Marie-Tooth disease, axonal, type 2Z, OMIM:616688
Penetrance for gene: MORC2 were set to Complete
Mode of pathogenicity for gene: MORC2 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: MORC2 was set to GREEN
gene: MORC2 was marked as current diagnostic
Added comment: Causes CMT2Z. Presents with prominent SMA-like proximal and distal weakness in adults, mimicking PMA. Needs inclusion in R460.1 to avoid R78 reanalysis.
Sources: Expert Review, Literature
Congenital muscular dystrophy v7.2 MCOLN1 Arina Puzriakova gene: MCOLN1 was added
gene: MCOLN1 was added to Congenital muscular dystrophy. Sources: NHS GMS
Mode of inheritance for gene: MCOLN1 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.8 MCOLN1 Arina Puzriakova gene: MCOLN1 was added
gene: MCOLN1 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: MCOLN1 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.7 JPH1 Arina Puzriakova Classified gene: JPH1 as No list
Congenital myopathy v7.7 JPH1 Arina Puzriakova Gene: jph1 has been removed from the panel.
Congenital myopathy v7.6 JPH1 Arina Puzriakova gene: JPH1 was added
gene: JPH1 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.5 HMGCS1 Arina Puzriakova Classified gene: HMGCS1 as No list
Congenital myopathy v7.5 HMGCS1 Arina Puzriakova Gene: hmgcs1 has been removed from the panel.
Adult onset neurodegenerative disorder v9.1 MME Oliver Ziff gene: MME was added
gene: MME was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: MME was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: MME were set to 26924531
Phenotypes for gene: MME were set to Charcot-Marie-Tooth disease, axonal, type 2T, OMIM:617017
Penetrance for gene: MME were set to Complete
Mode of pathogenicity for gene: MME 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: MME was set to GREEN
gene: MME was marked as current diagnostic
Added comment: MME variants frequently present as a late-onset >40 years motor-predominant axonal polyneuropathy. Because the clinical presentation features progressive distal lower motor neuron weakness and wasting in adulthood, it mimics Progressive Muscular Atrophy and LMN-variant MND. Adding it to the R460.1 panel is necessary to capture these mimics upfront and prevent sequential R78 WGS reanalysis for patients on the MND diagnostic pathway.
Sources: Expert Review, Literature
Congenital myopathy v7.4 HMGCS1 Arina Puzriakova gene: HMGCS1 was added
gene: HMGCS1 was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v7.3 CACNA1H Arina Puzriakova Classified gene: CACNA1H as No list
Congenital myopathy v7.3 CACNA1H Arina Puzriakova Gene: cacna1h has been removed from the panel.
Congenital myopathy v7.2 CACNA1H Arina Puzriakova gene: CACNA1H was added
gene: CACNA1H was added to Congenital myopathy. Sources: NHS GMS
Mode of inheritance for gene: CACNA1H was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset neurodegenerative disorder v9.1 UBA1 Oliver Ziff gene: UBA1 was added
gene: UBA1 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: UBA1 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: UBA1 were set to 18179898; 31932168; 26456228; 27797960; 35919735; 33108101
Phenotypes for gene: UBA1 were set to Spinal muscular atrophy, X-linked 2, OMIM:301830
Penetrance for gene: UBA1 were set to Complete
Mode of pathogenicity for gene: UBA1 was set to Other
Review for gene: UBA1 was set to GREEN
gene: UBA1 was marked as current diagnostic
Added comment: Germline UBA1 variants cause SMAX2, an anterior horn cell disorder that presents with progressive lower motor neuron degeneration. It is a direct clinical and biological mimic of PMA/LMN-variant ALS and should be included on the MND panel to prevent diagnostic misses. Needs inclusion in R460.1
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 NEFH Oliver Ziff reviewed gene: NEFH: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2CC, 616924; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Adult onset neurodegenerative disorder v9.1 ATP7A Oliver Ziff gene: ATP7A was added
gene: ATP7A was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: ATP7A 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: ATP7A were set to 20170900
Phenotypes for gene: ATP7A were set to Spinal muscular atrophy, X-linked 3, distal, OMIM:300489
Penetrance for gene: ATP7A were set to Complete
Mode of pathogenicity for gene: ATP7A was set to Other
Review for gene: ATP7A was set to GREEN
gene: ATP7A was marked as current diagnostic
Added comment: Specific missense variants cause X-linked distal motor neuropathy (SMAX3), mimicking adult LMN disease without systemic Menkes features. Needs inclusion in R460.1 to prevent R78 reanalysis.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 DYNC1H1 Oliver Ziff reviewed gene: DYNC1H1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 21820100, 26392352; Phenotypes: Charcot Marie Tooth disease, axonal, type 20, 614228, Mental retardation, autosomal dominant 13, 614563, Spinal muscular atrophy, lower extremity predominant, AD, 158600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Adult onset neurodegenerative disorder v9.1 IGHMBP2 Oliver Ziff gene: IGHMBP2 was added
gene: IGHMBP2 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: IGHMBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IGHMBP2 were set to 26392352; 34726235
Phenotypes for gene: IGHMBP2 were set to Charcot-Marie-Tooth disease, axonal, type 2S 616155; Neuronopathy, distal hereditary motor, type VI, 604320
Penetrance for gene: IGHMBP2 were set to Incomplete
Mode of pathogenicity for gene: IGHMBP2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Causes a slowly progressive adult-onset distal SMA. Phenotypically overlaps with LMN-variant MND. Needs inclusion in R460.1 ALS panel to avoid R78 reanalysis.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 SORD Oliver Ziff gene: SORD was added
gene: SORD was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to 323670585; 33314640; 33397963
Phenotypes for gene: SORD were set to Sorbitol dehydrogenase deficiency with peripheral neuropathy OMIM:618912; Neuropathy, distal hereditary motor, OMIM:158590
Penetrance for gene: SORD were set to Complete
Mode of pathogenicity for gene: SORD 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: SORD was set to GREEN
gene: SORD was marked as current diagnostic
Added comment: Prevalent cause of recessive dHMN/CMT2. It frequently presents as progressive LMN weakness in adulthood, making it a critical, potentially treatable ALS mimic. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 SYT2 Oliver Ziff gene: SYT2 was added
gene: SYT2 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: SYT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYT2 were set to 26519543; 30533528
Phenotypes for gene: SYT2 were set to Neuropathy, distal hereditary motor, OMIM:158590; Progressive muscular atrophy, OMIM:105400
Penetrance for gene: SYT2 were set to Complete
Mode of pathogenicity for gene: SYT2 was set to Other
Added comment: Presents as a slowly progressive distal motor neuropathy and LMN syndrome mimicking PMA. mimics LMN-predominant MND, necessitating upfront R460.1 screening.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 SLC5A7 Oliver Ziff gene: SLC5A7 was added
gene: SLC5A7 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: SLC5A7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC5A7 were set to 29782645; 23141292
Phenotypes for gene: SLC5A7 were set to Neuronopathy, distal hereditary motor, type VIIA
Penetrance for gene: SLC5A7 were set to Complete
Mode of pathogenicity for gene: SLC5A7 was set to Other
Review for gene: SLC5A7 was set to GREEN
gene: SLC5A7 was marked as current diagnostic
Added comment: Dominant negative variants cause a distal hereditary motor neuropathy (dHMN7A) mimicking progressive isolated LMN degeneration. mimics LMN-predominant MND, necessitating upfront screening. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 TRPV4 Oliver Ziff gene: TRPV4 was added
gene: TRPV4 was added to Adult onset neurodegenerative disorder. Sources: Literature,Expert Review
Mode of inheritance for gene: TRPV4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPV4 were set to 20037586
Phenotypes for gene: TRPV4 were set to Hereditary motor and sensory neuropathy, type IIc, 606071
Penetrance for gene: TRPV4 were set to Complete
Mode of pathogenicity for gene: TRPV4 was set to Other
Review for gene: TRPV4 was set to GREEN
gene: TRPV4 was marked as current diagnostic
Added comment: Causes scapuloperoneal SMA and dHMN. The progressive motor weakness frequently mimics LMN-predominant MND, necessitating upfront R460.1 screening. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Literature, Expert Review
Autoinflammatory disorders v3.9 OTULIN Ida Ertmanska changed review comment from: PMID: 38630025 Davidson et al., 2024
Report of 2 patients (unrelated, 1 Caucasian and 1 Saudi family) with het p.Cys129Ser (stemming from c.385T>A or c.386G>C) change in OTULIN and a presentation consistent with OTULIN-related autoinflammatory syndrome. Authors observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells. Patients presented with very early onset chronic inflammation, sterlie pustulosis, wound dehiscence. Variant is posed to have a dominant-negative effect.

PMID: 38914362 Caballero-Oteyza et al., 2024
Novel homozygous missense mutation OTULIN c.595T>A; p.(Trp199Arg) detected in a Moroccan infant with an ORAS phenotype of severe, sterile systemic inflammation, panniculitis. Method: WES + Sanger. Literature review in the paper includes 9 AR ORAS, 17 OTULIN Haploinsufficiency (AR Immunodeficiency) and 3 Dominant negative ORAS cases (including one from this study).; to: PMID: 38630025 Davidson et al., 2024
Report of 2 patients (unrelated, 1 Caucasian and 1 Saudi family) with het p.Cys129Ser (stemming from c.385T>A or c.386G>C) change in OTULIN and a presentation consistent with OTULIN-related autoinflammatory syndrome. Authors observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells. Patients presented with very early onset chronic inflammation, sterlie pustulosis, wound dehiscence. Variant is posed to have a dominant-negative effect.

PMID: 38914362 Caballero-Oteyza et al., 2024
Novel homozygous missense mutation OTULIN c.595T>A; p.(Trp199Arg) detected in a Moroccan infant with an ORAS phenotype of severe, sterile systemic inflammation, panniculitis. Method: WES + Sanger. Literature review in the paper includes 9 AR ORAS, 17 OTULIN Haploinsufficiency (AR Immunodeficiency) and 3 Dominant negative ORAS cases (including one from this study).

OMIM has associations for OTULIN-related Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, OMIM:617099 and Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, OMIM:621030 (accessed 22nd May 2026).
Adult onset neurodegenerative disorder v9.1 PLEKHG5 Oliver Ziff gene: PLEKHG5 was added
gene: PLEKHG5 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: PLEKHG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHG5 were set to 23844677; 17564964
Phenotypes for gene: PLEKHG5 were set to Charcot Marie Tooth disease, recessive intermediate C, 615376; Spinal muscular atrophy, distal, autosomal recessive, 4, 611067
Penetrance for gene: PLEKHG5 were set to Complete
Mode of pathogenicity for gene: PLEKHG5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Causes a late-onset distal hereditary motor neuropathy and SMA with progressive LMN signs that mimic PMA. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 HSPB8 Oliver Ziff gene: HSPB8 was added
gene: HSPB8 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: HSPB8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HSPB8 were set to Charcot Marie Tooth disease, axonal, type 2L, 608673; Neuropathy, distal hereditary motor, type IIA, 158590; Neuropathy, distal hereditary motor, type IIA, 158590
Penetrance for gene: HSPB8 were set to Incomplete
Mode of pathogenicity for gene: HSPB8 was set to Other
Review for gene: HSPB8 was set to GREEN
Added comment: Heat shock protein variant classically present with a late-onset, progressive lower motor neuron phenotype that clinically mimics progressive muscular atrophy. Inclusion prevents sequential WGS reanalysis on R460.1 requests.
Sources: Expert Review, Literature
Adult onset neurodegenerative disorder v9.1 SIGMAR1 Oliver Ziff reviewed gene: SIGMAR1: 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: 26205306, 21842496, 26088964, 25678561, 26088963, 26078401; Phenotypes: Neuropathy, distal hereditary motor, type IIB, OMIM:608634, Charcot-Marie-Tooth disease, type 2F, OMIM:606595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v9.1 HSPB1 Oliver Ziff gene: HSPB1 was added
gene: HSPB1 was added to Adult onset neurodegenerative disorder. Sources: Expert Review,Literature
Mode of inheritance for gene: HSPB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HSPB1 were set to 15122254; 28379183
Phenotypes for gene: HSPB1 were set to Neuropathy, distal hereditary motor, type IIB, OMIM:608634; Charcot-Marie-Tooth disease, type 2F, OMIM:606595
Penetrance for gene: HSPB1 were set to Incomplete
Mode of pathogenicity for gene: HSPB1 was set to Other
Review for gene: HSPB1 was set to GREEN
gene: HSPB1 was marked as current diagnostic
Added comment: HSPB1 variants (typically toxic gain-of-function missense mutations) frequently present with a late-onset, progressive lower motor neuron phenotype that clinically mimics progressive muscular atrophy (PMA) and ALS. Adding this target to the Adult onset neurodegenerative disorder component panel is necessary to capture these LMN mimics upfront on WGS requests for suspected MND (R460.1), preventing sequential and costly WGS reanalysis requests for the neuropathy panel (R78).
Sources: Expert Review, Literature
Proteinuric renal disease v6.1 STS John Sayer gene: STS was added
gene: STS was added to Proteinuric renal disease. Sources: Expert list
Mode of inheritance for gene: STS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STS were set to 22419362; 17468528
Phenotypes for gene: STS were set to Proteinuria; ichthyosis
Penetrance for gene: STS were set to Complete
Review for gene: STS was set to GREEN
Added comment: Good evidence this is a proteinuric gene. Cases of whole gene deletion of STS in Genomics England with phenotypes.
Sources: Expert list
Autoinflammatory disorders v3.9 OTULIN Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 22nd May 2026.
Autoinflammatory disorders v3.9 OTULIN Ida Ertmanska Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, OMIM:617099 to Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, OMIM:617099; Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, OMIM:621030
Autoinflammatory disorders v3.8 OTULIN Ida Ertmanska Publications for gene: OTULIN were set to 27559085; 27523608
Autoinflammatory disorders v3.7 OTULIN Ida Ertmanska Tag Q2_26_MOI tag was added to gene: OTULIN.
Autoinflammatory disorders v3.7 OTULIN Ida Ertmanska commented on gene: OTULIN: Comment on mode of inheritance: There are now 3 unrelated individuals reported with heterozygous missense (putative dominant-negative) variants in OTULIN, and an ORAS-like autoinflammatory syndrome. Hence, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on Autoinflammatory disorders.
Autoinflammatory disorders v3.7 OTULIN Ida Ertmanska reviewed gene: OTULIN: Rating: GREEN; Mode of pathogenicity: None; Publications: 38630025, 38914362; Phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, OMIM:617099, Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, OMIM:621030; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v4.19 CARD11 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: CARD11.
Rare genetic inflammatory skin disorders v4.19 CARD11 Ida Ertmanska commented on gene: CARD11: Comment on mode of inheritance: There are at least 3 unrelated individuals reported in literature with biallelic CARD11 variants and inflammatory skin presentation (severe atopic dermatitis, lichenification of the palms and soles). In 1 case, dermatitis was the main phenotype, with no severe recurrent infections noted. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on Rare genetic inflammatory skin disorders.
Rare genetic inflammatory skin disorders v4.19 CARD11 Ida Ertmanska Publications for gene: CARD11 were set to 28628108
Rare genetic inflammatory skin disorders v4.18 CARD11 Ida Ertmanska reviewed gene: CARD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 26289640, 36729250, https://doi.org/10.1186/s43042-024-00489-3, https://doi.org/10.4049/jimmunol.212.supp.0307.5377; Phenotypes: Immunodeficiency 11B with atopic dermatitis, OMIM:617638, Immunodeficiency 11A, OMIM:615206; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v7.10 GRHL2 Ida Ertmanska Phenotypes for gene: GRHL2 were changed from ECTODERMAL DYSPLASIA/SHORT STATURE SYNDROME to Ectodermal dysplasia/short stature syndrome, OMIM:616029
Fetal anomalies v7.9 GRHL2 Ida Ertmanska Publications for gene: GRHL2 were set to
Fetal anomalies v7.8 GRHL2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: GRHL2.
Fetal anomalies v7.8 GRHL2 Ida Ertmanska reviewed gene: GRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152456, 27612988; Phenotypes: Ectodermal dysplasia/short stature syndrome, OMIM:616029; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v6.13 GRHL2 Ida Ertmanska Publications for gene: GRHL2 were set to PMID:12393799; 20938050; 21610158; 23813623; 25152456
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska edited their review of gene: GRHL2: Changed publications to: 12393799, 23813623, 25152456, 27612988, 27911912, 32048449
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska changed review comment from: PMID: 25152456 Petros et al., 2013
2 consanguineous Kuwaiti families with 6 total affected individuals with ectodermal dysplasia. Shared features: nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, short stature (≤25th percentile), and dysphagia. Patients in family ED-01 also presented with sensorineural deafness. ED-01 members were homozygous for GRHL2 c.1192T>C (p.Tyr398His), and ED-02 were homozygous for c.1445T>A (p.Ile482Lys).

PMID: 27612988 Walne et al., 2016
Report of 2 consanguineous families from Kuwait and Turkey.
Family 9: index patient homozygous for GRHL2 c.1445T>A p.Ile482Lys
Family 10: index patient homozygous for GRHL2 c.1213C>A p.Pro405Thr
Shared phenotype of the 2 probands: abnormal dentition, nail dystrophy, abnormal skin pigmentation, growth restriction (short stature). No mention of hearing loss.; to: BIALLELIC CASES:
PMID: 25152456 Petros et al., 2013
2 consanguineous Kuwaiti families with 6 total affected individuals with ectodermal dysplasia. Shared features: nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, short stature (≤25th percentile), and dysphagia. Patients in family ED-01 also presented with sensorineural deafness. ED-01 members were homozygous for GRHL2 c.1192T>C (p.Tyr398His), and ED-02 were homozygous for c.1445T>A (p.Ile482Lys).

PMID: 27612988 Walne et al., 2016
Report of 2 consanguineous families from Kuwait and Turkey.
Family 9: index patient homozygous for GRHL2 c.1445T>A p.Ile482Lys
Family 10: index patient homozygous for GRHL2 c.1213C>A p.Pro405Thr
Shared phenotype of the 2 probands: abnormal dentition, nail dystrophy, abnormal skin pigmentation, growth restriction (short stature). No mention of hearing loss.

MONOALLELIC CASES:
PMID: 12393799 Peters et al., 2002
Large American family with an autosomal dominant form of progressive non-syndromic sensorineural hearing loss. Variant c.1609-1610insC in GRHL2 (old name TFCP2L3) segregated with hearing loss.

PMID: 23813623 Vona et al., 2013
Large pedigree with post-lingual hearing loss with a highly variable age of onset and progression - segregated with a heterozygous non-classical splice site mutation in GRHL2: c.1258-1G>A, p.Gly420Glufs*111.

PMID: 27911912 Iwasa et al., 2016
3 Japanese families with AD hearing loss and heterozygous GRHL2 variants (2 missense, 1 frameshift)

PMID: 32048449 Wu et al., 2020
Han Chinese family with AD non-syndromic deafness, a het GRHL2 p.R426X variant segregated with hearing loss.
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska commented on gene: GRHL2: Comment on mode of inheritance: While there are several individuals reported with monoallelic GRHL2 variants and hearing loss, only 1/4 families reported with biallelic variants presented with hearing loss. Hence, the MOI for Monogenic hearing loss should be changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: GRHL2.
Monogenic hearing loss v6.12 GRHL2 Ida Ertmanska reviewed gene: GRHL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25152456, 27612988; Phenotypes: Ectodermal dysplasia/short stature syndrome, OMIM:616029; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ehlers Danlos syndrome with a likely monogenic cause v4.9 LOX Ida Ertmanska Publications for gene: LOX were set to 26838787; 27432961
Ehlers Danlos syndrome with a likely monogenic cause v4.8 LOX Ida Ertmanska Tag Q2_26_MOI tag was added to gene: LOX.
Ehlers Danlos syndrome with a likely monogenic cause v4.8 LOX Ida Ertmanska commented on gene: LOX: Comment on mode of inheritance: There are 2 unrelated probands reported with biallelic missense LOX variants and a shared phenotype of cutis laxa, arterial dilatation, thickened heart, bone fragility, and respiratory failure. Mouse models are supportive, with knockout mouse showing abnormal collagen fibers in skin, impaired airway development, aneurysms and aortic wall dysplasia, with death occuring shortly after birth. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ehlers Danlos syndrome with a likely monogenic cause v4.8 LOX Ida Ertmanska reviewed gene: LOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 16192629, 27432961, 33866545; Phenotypes: Aortic aneurysm, familial thoracic 10, OMIM:617168; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v5.3 LOX Ida Ertmanska Phenotypes for gene: LOX were changed from Aortic aneurysm, familial thoracic 10, 617168; aortic aneurysm to Aortic aneurysm, familial thoracic 10, OMIM:617168
Thoracic aortic aneurysm or dissection (GMS) v5.2 LOX Ida Ertmanska Publications for gene: LOX were set to 26838787; 27432961
Thoracic aortic aneurysm or dissection (GMS) v5.1 LOX Ida Ertmanska Tag Q2_26_MOI tag was added to gene: LOX.
Thoracic aortic aneurysm or dissection (GMS) v5.1 LOX Ida Ertmanska commented on gene: LOX: Comment on mode of inheritance: There are 2 unrelated probands reported with biallelic missense LOX variants and a shared phenotype of cutis laxa, arterial dilatation, thickened heart, bone fragility, and respiratory failure. Mouse models are supportive, with knockout mouse showing abnormal collagen fibers in skin, impaired airway development, aneurysms and aortic wall dysplasia, with death occuring shortly after birth. Hence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Thoracic aortic aneurysm or dissection (GMS) v5.1 LOX Ida Ertmanska reviewed gene: LOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 16192629, 27432961, 33866545; Phenotypes: Aortic aneurysm, familial thoracic 10, OMIM:617168; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric motor neuronopathies v3.16 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: A 'treatable' tag was added as high-dose riboflavin supplementation early on is effective in stopping disease progression and possibly lifesaving (https://www.ncbi.nlm.nih.gov/books/NBK299312/).
Monogenic hearing loss v6.12 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: A 'treatable' tag was added as high-dose riboflavin supplementation early on is effective in stopping disease progression and possibly lifesaving (https://www.ncbi.nlm.nih.gov/books/NBK299312/).
Hereditary neuropathy or pain disorder v8.3 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: A 'treatable' tag was added as high-dose riboflavin supplementation early on is effective in stopping disease progression and possibly lifesaving (https://www.ncbi.nlm.nih.gov/books/NBK299312/).
Likely inborn error of metabolism v9.4 SLC52A3 Ida Ertmanska Tag treatable tag was added to gene: SLC52A3.
Likely inborn error of metabolism v9.4 SLC52A3 Ida Ertmanska commented on gene: SLC52A3
Mitochondrial disorders v10.4 SLC52A3 Ida Ertmanska commented on gene: SLC52A3
Mitochondrial disorders v10.4 SLC52A3 Ida Ertmanska Tag treatable tag was added to gene: SLC52A3.
Paediatric motor neuronopathies v3.16 SLC52A3 Ida Ertmanska Phenotypes for gene: SLC52A3 were changed from Brown-Vialetto-Van Laere syndrome 1, OMIM:211530 to Brown-Vialetto-Van Laere syndrome 1, OMIM:211530; Brown-Vialetto-van Laere syndrome 1, MONDO:0024537; ?Fazio-Londe disease, OMIM:211500; riboflavin transporter deficiency, MONDO:0008891
Paediatric motor neuronopathies v3.15 SLC52A3 Ida Ertmanska Publications for gene: SLC52A3 were set to 20206331; 20920669
Paediatric motor neuronopathies v3.14 SLC52A3 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: SLC52A3.
Paediatric motor neuronopathies v3.14 SLC52A3 Ida Ertmanska Tag treatable tag was added to gene: SLC52A3.
Hereditary neuropathy or pain disorder v8.3 SLC52A3 Ida Ertmanska Phenotypes for gene: SLC52A3 were changed from Fazio-Londe disease; dHMN; Brown-Vialetto-Van Laere syndrome 1 to Brown-Vialetto-Van Laere syndrome 1, OMIM:211530; Brown-Vialetto-van Laere syndrome 1, MONDO:0024537; ?Fazio-Londe disease, OMIM:211500; riboflavin transporter deficiency, MONDO:0008891
Hereditary neuropathy or pain disorder v8.2 SLC52A3 Ida Ertmanska Publications for gene: SLC52A3 were set to 20206331
Hereditary neuropathy or pain disorder v8.1 SLC52A3 Ida Ertmanska Tag treatable tag was added to gene: SLC52A3.
Tag Q2_26_MOI tag was added to gene: SLC52A3.
Paediatric motor neuronopathies v3.14 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: Comment on mode of inheritance: There are more than 3 unrelated patients with both monoallelic and biallelic variants in SLC52A3 and Brown-Vialetto-Van Laere syndrome. Both modes of inheritance result in the same phenotype of hearing loss and ponto-bulbar palsy / bilateral vestibular neuropathy. Hence, the mode of inheritance for Paediatric motor neuronopathies should be updated from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v8.1 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: Comment on mode of inheritance: There are more than 3 unrelated patients with both monoallelic and biallelic variants in SLC52A3 and Brown-Vialetto-Van Laere syndrome. Both modes of inheritance result in the same phenotype of hearing loss and ponto-bulbar palsy / bilateral vestibular neuropathy. Hence, the mode of inheritance for Hereditary neuropathy or pain disorder should be updated from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v8.1 SLC52A3 Ida Ertmanska reviewed gene: SLC52A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22718020, 29053833, 34384672, 38469093, 40539137; Phenotypes: Brown-Vialetto-Van Laere syndrome 1, OMIM:211530, Brown-Vialetto-van Laere syndrome 1, MONDO:0024537, ?Fazio-Londe disease, OMIM:211500, riboflavin transporter deficiency, MONDO:0008891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric motor neuronopathies v3.14 SLC52A3 Ida Ertmanska reviewed gene: SLC52A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22718020, 29053833, 34384672, 38469093, 40539137; Phenotypes: Brown-Vialetto-Van Laere syndrome 1, OMIM:211530, Brown-Vialetto-van Laere syndrome 1, MONDO:0024537, ?Fazio-Londe disease, OMIM:211500, riboflavin transporter deficiency, MONDO:0008891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v6.12 SLC52A3 Ida Ertmanska Publications for gene: SLC52A3 were set to 20206331; 20920669
Monogenic hearing loss v6.11 SLC52A3 Ida Ertmanska Phenotypes for gene: SLC52A3 were changed from Brown-Vialetto-Van Laere syndrome 1, OMIM:211530 to Brown-Vialetto-Van Laere syndrome 1, OMIM:211530; Brown-Vialetto-van Laere syndrome 1, MONDO:0024537; ?Fazio-Londe disease, OMIM:211500; riboflavin transporter deficiency, MONDO:0008891
Monogenic hearing loss v6.10 SLC52A3 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: SLC52A3.
Monogenic hearing loss v6.10 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: Comment on mode of inheritance: There are more than 3 unrelated patients with both monoallelic and biallelic variants in SLC52A3 and Brown-Vialetto-Van Laere syndrome. Both modes of inheritance result in the same phenotype of hearing loss and ponto-bulbar palsy / bilateral vestibular neuropathy. Hence, the mode of inheritance for Monogenic hearing loss should be updated from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Monogenic hearing loss v6.10 SLC52A3 Ida Ertmanska reviewed gene: SLC52A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22718020, 29053833, 34384672, 38469093, 40539137; Phenotypes: Brown-Vialetto-Van Laere syndrome 1, OMIM:211530, Brown-Vialetto-van Laere syndrome 1, MONDO:0024537, ?Fazio-Londe disease, OMIM:211500, riboflavin transporter deficiency, MONDO:0008891; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Palmoplantar keratodermas v4.11 KRT10 Ida Ertmanska Phenotypes for gene: KRT10 were changed from Pachyonychia congenita; Palmoplantar keratoderma; Ichythosis with confetti; Epidermolytic hyperkeratosis to Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707; Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150
Palmoplantar keratodermas v4.10 KRT10 Ida Ertmanska Publications for gene: KRT10 were set to
Palmoplantar keratodermas v4.9 KRT10 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: KRT10.
Palmoplantar keratodermas v4.9 KRT10 Ida Ertmanska commented on gene: KRT10: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and epidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with erosion improvement later in life and progressive hyperkeratosis (often on scalp and palmoplantar). Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Palmoplantar keratodermas v4.9 KRT10 Ida Ertmanska reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: None; Publications: 16505000, 20302579, 23957016, 29277919, 34273205, 38741524; Phenotypes: Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707, Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v4.14 KRT10 Ida Ertmanska Phenotypes for gene: KRT10 were changed from Epidermolytic hyperkeratosis (EHK), OMIM:113800; ichthyosis with confetti, OMIM:609165; Ichthyosis, cyclic, with epidermolytic hyperkeratosis, OMIM:607602 to Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707; Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150
Ichthyosis and erythrokeratoderma v4.13 KRT10 Ida Ertmanska Publications for gene: KRT10 were set to
Ichthyosis and erythrokeratoderma v4.12 KRT10 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: KRT10.
Epidermolysis bullosa and congenital skin fragility v2.15 KRT10 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and pidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with improvement later in life. Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and epidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with improvement later in life. Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ichthyosis and erythrokeratoderma v4.12 KRT10 Ida Ertmanska commented on gene: KRT10: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and epidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with improvement later in life (progression to hyperkeratosis). Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Ichthyosis and erythrokeratoderma v4.12 KRT10 Ida Ertmanska reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: None; Publications: 16505000, 20302579, 23957016, 29277919, 34273205, 38741524; Phenotypes: Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707, Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Epidermolysis bullosa and congenital skin fragility v2.15 KRT10 Ida Ertmanska edited their review of gene: KRT10: Changed publications to: 16505000, 20302579, 23957016, 29277919, 34273205, 38741524
Epidermolysis bullosa and congenital skin fragility v2.15 KRT10 Ida Ertmanska commented on gene: KRT10: Comment on mode of inheritance: There are more than 3 unrelated individuals with biallelic KRT10 variants and pidermolytic ichthyosis / hyperkeratosis - heterozygous family members were unaffected. Most individuals presented with generalized erythema, erosions, scaling and easily breaking blisters, with improvement later in life. Based on available evidence, the MOI should be updated from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Epidermolysis bullosa and congenital skin fragility v2.15 KRT10 Ida Ertmanska Phenotypes for gene: KRT10 were changed from Epidermolytic hyperkeratosis, OMIM:113800 to Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707; Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150
Epidermolysis bullosa and congenital skin fragility v2.14 KRT10 Ida Ertmanska Publications for gene: KRT10 were set to
Epidermolysis bullosa and congenital skin fragility v2.13 KRT10 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: KRT10.
Epidermolysis bullosa and congenital skin fragility v2.13 KRT10 Ida Ertmanska reviewed gene: KRT10: Rating: GREEN; Mode of pathogenicity: None; Publications: 16505000, 20302579, 29277919, 34273205, 38741524; Phenotypes: Epidermolytic hyperkeratosis 2B, autosomal recessive, OMIM:620707, Epidermolytic hyperkeratosis 2A, autosomal dominant, OMIM:620150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cholestasis v4.5 PEX6 Ida Ertmanska Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger) 614862 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Cholestasis v4.4 PEX6 Ida Ertmanska Publications for gene: PEX6 were set to 10408779; 8670792; 8940266
Cholestasis v4.3 PEX6 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: PEX6.
Cholestasis v4.3 PEX6 Ida Ertmanska commented on gene: PEX6: Comment on mode of inheritance: As there are 5 unrelated families reported in PMID: 29220678 with monoallelic PEX6 variants and apparently dominant Zellweger syndrome with hepatomegaly/liver dysfunction, the MOI should be changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Cholestasis v4.3 PEX6 Ida Ertmanska reviewed gene: PEX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29220678; Phenotypes: Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862, Peroxisome biogenesis disorder 4B, OMIM:614863; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v7.8 RET Ida Ertmanska commented on gene: RET: Comment on mode of inheritance: I have found very limited evidence of RET-related recessive disease - 2 cases of severe Hirschsprung disease, and no cases with biallelic RET variants and renal agenesis. Hence, the MOI should be changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.
Fetal anomalies v7.8 RET Ida Ertmanska Publications for gene: RET were set to
Fetal anomalies v7.7 RET Ida Ertmanska Tag Q2_26_MOI tag was added to gene: RET.
Paediatric pseudo-obstruction syndrome v2.6 RET Ida Ertmanska Tag Q2_26_MOI was removed from gene: RET.
Paediatric pseudo-obstruction syndrome v2.6 RET Ida Ertmanska Tag Q2_26_MOI tag was added to gene: RET.
Fetal anomalies v7.7 RET Ida Ertmanska reviewed gene: RET: Rating: GREEN; Mode of pathogenicity: None; Publications: 9090527, 34267336; Phenotypes: {Hirschsprung disease, susceptibility to, 1}, OMIM:142623; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric pseudo-obstruction syndrome v2.6 RET Ida Ertmanska reviewed gene: RET: Rating: GREEN; Mode of pathogenicity: None; Publications: 9090527, 34267336; Phenotypes: {Hirschsprung disease, susceptibility to, 1}, OMIM:142623; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypogonadotropic hypogonadism (GMS) v5.2 PROKR2 Ida Ertmanska commented on gene: PROKR2: Comment on mode of inheritance: The majority (up to 90%) of cases reported in literature with Hypogonadotropic hypogonadism and PROKR2 variants are heterozygotes. There are at least 22 patients with HH and biallelic PROKR2 variants - mostly biallelic missense. Hence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.
Hypogonadotropic hypogonadism (GMS) v5.2 PROKR2 Ida Ertmanska Publications for gene: PROKR2 were set to 36694982
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: PROKR2.
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska changed review comment from: PMID: 36843573 Martinez-Mayer and Perez-Millan, 2023
Literature review of 435 cases with PROKR2 variants, 108 with hypogonadotropic hypogonadism (HH) and 236 with Kallmann syndrome (KS). 90% of cases are heterozygous, 7% homozygous and 3% comp het.

Biallelic case examples:
PMID: 18682503 Abreu et al., 2008
PROKR2 p.Y140X change was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous.

PMID: 35236788 Sugisawa et al., 2022
We describe the case of a 31-year-old man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. Diagnosed with sexual immaturity at 20 yrs old. He was comp het for PROKR2 variants p.Trp178Ser and p.Trp212*.

PROKR2 is associated with AD,AR Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200 (accessed 20th May 2026).; to: PMID: 36843573 Martinez-Mayer and Perez-Millan, 2023
Literature review of 435 cases with PROKR2 variants, 108 with hypogonadotropic hypogonadism (HH) and 236 with Kallmann syndrome (KS). 90% of cases are heterozygous, 7% homozygous and 3% comp het.

Biallelic case examples:
PMID: 18682503 Abreu et al., 2008
PROKR2 p.Y140X change was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous.

PMID: 35236788 Sugisawa et al., 2022
Report of a case of a 31-year-old Japanese man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. Diagnosed with sexual immaturity at 20 yrs old. He was comp het for PROKR2 variants p.Trp178Ser and p.Trp212*.
Literature review in same article found 21 other patients from 17 families with biallelic PROKR2 variants and CHH (86% diagnosed with KS). 17/22 patients had missense variants on both alleles; only 1 had biallelic truncating variants.

PROKR2 is associated with AD,AR Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200 (accessed 20th May 2026).
Hypogonadotropic hypogonadism (GMS) v5.1 PROKR2 Ida Ertmanska reviewed gene: PROKR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18682503, 35236788, 36843573; Phenotypes: Hypogonadotropic hypogonadism 3 with or without anosmia, OMIM:244200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare anaemia v4.2 SLC4A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - compensated hemolysis and spherocytosis were incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.; to: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - some had mild hematological incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.
Rare anaemia v4.2 SLC4A1 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - compensated hemolysis and spherocytosis were incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.; to: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - compensated hemolysis and spherocytosis were incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.
Rare anaemia v4.2 SLC4A1 Ida Ertmanska edited their review of gene: SLC4A1: Changed publications to: 37448902, 36776909, 29483102, 18174378, 16252102
Rare anaemia v4.2 SLC4A1 Ida Ertmanska changed review comment from: Biallelic anaemia cases:
PMID: 37448902 Shaikh, Suratkal, and Bhave, 2023
Report of an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia. The patient was treated for suspicion of autoimmune hemolytic anemia but was recalcitrant to treatment. Genetic analysis revealed the patient to be homozygous for SLC4A1 c.2573C>A (p.Ala858Asp). The patient’s parents and siblings had no clinical history of hematological or renal disease.

PMID: 29483102 Yang et al., 2018
Patient with anemia and distal renal tubular acidosis, homozygous for SLC4A1 c.2173A>C, p.Ser725Arg. 6-day-old male infant presented with tachypnea, intermittent hypoxia, scleral icterus, splenomegaly, and severe anemia, hemoglobin 6.6 g/dL, and marked spherocytosis. Mother and father (first cousins from Pakistan) were het for the variant, also had Band 3 deficiency and a level of hemolysis, though much lower than in the proband.

PMID: 18174378 Toye et al., 2008
Proband developed a transfusion-dependent, hemolytic anemia following birth. Immunoblotting showed band 3 was reduced to approximately 35% of wildtype. Homozygous SLC4A1 c.2000C>T, p.Ser667Phe variant detected. Parents are first cousins from Algerina, both het for the variant - showed compensated hemolysis and spherocytosis, which they were unaware of.; to: Biallelic anaemia cases:
PMID: 37448902 Shaikh, Suratkal, and Bhave, 2023
Report of an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia. The patient was treated for suspicion of autoimmune hemolytic anemia but was recalcitrant to treatment. Genetic analysis revealed the patient to be homozygous for SLC4A1 c.2573C>A (p.Ala858Asp). The patient’s parents and siblings had no clinical history of hematological or renal disease.

PMID: 36776909 Yang et al., 2023 - literature review
"almost half of the patients with AR dRTA had hematological abnormalities, while it was uncommon in patients with AD dRTA'
dRTA = distal renal tubular acidosis
"Autosomal recessive inheritance was more often found in Asian patients (P < 0.05)."

PMID: 29483102 Yang et al., 2018
Patient with anemia and distal renal tubular acidosis, homozygous for SLC4A1 c.2173A>C, p.Ser725Arg. 6-day-old male infant presented with tachypnea, intermittent hypoxia, scleral icterus, splenomegaly, and severe anemia, hemoglobin 6.6 g/dL, and marked spherocytosis. Mother and father (first cousins from Pakistan) were het for the variant, also had Band 3 deficiency and a level of hemolysis, though much lower than in the proband.

PMID: 22126643 Fawaz et al., 2012
Study of 7 children from 5 consanguineous Omani families presenting with hyperchloremic normal anion gap metabolic acidosis, failure to thrive, and mild to moderate compensated hemolytic anemia, homozygous for c.2573C>A; p.Ala858Asp (confirmed het in all parents). Reported striking acanthocytosis in the homozygous state and only a mild acanthocytosis in parents.

PMID: 18174378 Toye et al., 2008
Proband developed a transfusion-dependent, hemolytic anemia following birth. Immunoblotting showed band 3 was reduced to approximately 35% of wildtype. Homozygous SLC4A1 c.2000C>T, p.Ser667Phe variant detected. Parents are first cousins from Algerina, both het for the variant - showed compensated hemolysis and spherocytosis, which they were unaware of.

PMID: 16252102 Choo et al., 2005
Patient 2, Sarawak boy with profound hemolytic anemia - comp het for SLC4A1 p.Q759H and p.Ala400_Ala408del variants. Admitted to hospital at 3 weeks due to anemia and failure to thrive, required blood transfusions.
Rare anaemia v4.2 SLC4A1 Ida Ertmanska commented on gene: SLC4A1: Comment on mode of inheritance: There are at least 3 unrelated probands reported in literature with biallelic SLC4A1 variants and severe early onset hemolytic anemia with spherocytosis. Heterozygous family members did not show symptoms of hematological or renal disease - compensated hemolysis and spherocytosis were incidental findings. Hence, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form)', autosomal or pseudoautosomal to reflect this.
Rare anaemia v4.2 SLC4A1 Ida Ertmanska Publications for gene: SLC4A1 were set to 1722314
Rare anaemia v4.1 SLC4A1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: SLC4A1.
Rare anaemia v4.1 SLC4A1 Ida Ertmanska reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37448902, 29483102, 18174378; Phenotypes: Distal renal tubular acidosis 4 with hemolytic anemia, OMIM:611590, Cryohydrocytosis, OMIM:185020, Spherocytosis, type 4, OMIM:612653; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v9.3 MAB21L1 Achchuthan Shanmugasundram Classified gene: MAB21L1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v9.3 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are nine patients from six unrelated families reported with cerebellar anomalies and with biallelic MAB21L1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v9.3 MAB21L1 Achchuthan Shanmugasundram Gene: mab21l1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v9.2 MAB21L1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MAB21L1.
Ataxia and cerebellar anomalies - narrow panel v9.2 MAB21L1 Achchuthan Shanmugasundram gene: MAB21L1 was added
gene: MAB21L1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAB21L1 were set to 27103078; 30487245
Phenotypes for gene: MAB21L1 were set to Cerebellar, ocular, craniofacial, and genital syndrome, OMIM:618479; cerebellar, ocular, craniofacial, and genital syndrome, MONDO:0032774
Review for gene: MAB21L1 was set to GREEN
Added comment: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in an 8-year-old Algerian boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from five consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cerebellar anomalies such as cerebellar hypoplasia/ Dandy-Walker malformation/ Cerebellovermian hypoplasia with/ without pontine involvement was reported in eight patients from five families.

Biallelic variants in this gene are associated with relevant phenotypes in OMIM (MIM #618479, last accessed 19 May 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and ClinGen (Strong rating by Syndromic disorders Expert panel - https://search.clinicalgenome.org/CCID:008388)
Sources: Literature
Cytopenia - NOT Fanconi anaemia v5.2 TUBA4A Achchuthan Shanmugasundram edited their review of gene: TUBA4A: Changed rating: AMBER
Cytopenia - NOT Fanconi anaemia v5.2 TUBA4A Achchuthan Shanmugasundram Classified gene: TUBA4A as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v5.2 TUBA4A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Carl Fratter on Bleeding and platelet disorders panel (https://panelapp.genomicsengland.co.uk/panels/545/gene/TUBA4A/), there is only one published human case of macrothrombocytopenia and functional evidence from mouse model reported in association with variants in TUBA4A gene. This gene has been classified with 'Limited' rating by the Hemostasis Thrombosis expert panel in ClinGen. This gene can therefore be rated amber with the current evidence.
Cytopenia - NOT Fanconi anaemia v5.2 TUBA4A Achchuthan Shanmugasundram Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Alexander Symon-Allen, there are 4 unrelated individuals reported in literature with monoallelic KCNJ4 variants and epilepsy. Hence, this gene should be promoted to Green at the next GMS update.; to: Comment on list classification: As reviewed by Alexander Symon-Allen, there are 4 unrelated individuals reported in literature with monoallelic KCNJ4 variants and early-onset epilepsy. Hence, this gene should be promoted to Green at the next GMS update.
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska edited their review of gene: KCNJ4: Changed rating: GREEN
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: KCNJ4.
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska Classified gene: KCNJ4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Alexander Symon-Allen, there are 4 unrelated individuals reported in literature with monoallelic KCNJ4 variants and epilepsy. Hence, this gene should be promoted to Green at the next GMS update.
Early onset or syndromic epilepsy v9.7 KCNJ4 Ida Ertmanska Gene: kcnj4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.6 SCN9A Ida Ertmanska Tag refuted tag was added to gene: SCN9A.
Malformations of cortical development v8.3 CEP76 Ida Ertmanska edited their review of gene: CEP76: Changed rating: RED
Malformations of cortical development v8.3 CEP76 Ida Ertmanska changed review comment from: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed non-cortical brain anomalies including molar tooth sign (brainstem and cerebellum anomaly), cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene can only be rated Red for Malformations of cortical development.; to: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed non-cortical brain anomalies including molar tooth sign (brainstem and cerebellum anomaly), cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene is not relevant to this panel - a curate_removed tag has been added.
Malformations of cortical development v8.3 CEP76 Ida Ertmanska Classified gene: CEP76 as No list
Malformations of cortical development v8.3 CEP76 Ida Ertmanska Gene: cep76 has been removed from the panel.
Malformations of cortical development v8.2 CEP76 Ida Ertmanska Tag curated_removed tag was added to gene: CEP76.
Malformations of cortical development v8.2 CEP76 Ida Ertmanska Classified gene: CEP76 as Red List (low evidence)
Malformations of cortical development v8.2 CEP76 Ida Ertmanska Gene: cep76 has been classified as Red List (Low Evidence).
Malformations of cortical development v8.1 CEP76 Ida Ertmanska changed review comment from: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed cortical anomalies including molar tooth sign, cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene should be promoted to Green for Malformations of cortical development.; to: Comment on list classification: There are 8 unrelated patients reported in literature with biallelic CEP76 variants and syndromic ciliopathy, with prevalent ocular and neurodevelopmental features. 5 patients showed non-cortical brain anomalies including molar tooth sign (brainstem and cerebellum anomaly), cerebellar vermis hypoplasia, and abnormal brain stem. Based on available evidence, this gene can only be rated Red for Malformations of cortical development.
Malformations of cortical development v8.1 CEP76 Ida Ertmanska Tag Q1_26_promote_green was removed from gene: CEP76.
Fetal anomalies v7.7 LMNB2 Arina Puzriakova Tag watchlist_moi tag was added to gene: LMNB2.
Early onset or syndromic epilepsy v9.6 EIF4A2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 18th May 2026.
Early onset or syndromic epilepsy v9.6 EIF4A2 Ida Ertmanska Phenotypes for gene: EIF4A2 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, OMIM:620455; neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, MONDO:0957541
Intellectual disability v10.17 EIF4A2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 18th May 2026.
Intellectual disability v10.17 EIF4A2 Ida Ertmanska Phenotypes for gene: EIF4A2 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, OMIM:620455; neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, MONDO:0957541
Childhood onset hereditary spastic paraplegia v9.1 DSTYK Ida Ertmanska Tag founder-effect tag was added to gene: DSTYK.
Hypertrophic cardiomyopathy v6.2 MYPN Ida Ertmanska Tag disputed tag was added to gene: MYPN.
Hypertrophic cardiomyopathy v6.2 MYPN Ida Ertmanska Classified gene: MYPN as Red List (low evidence)
Hypertrophic cardiomyopathy v6.2 MYPN Ida Ertmanska Gene: mypn has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy v6.1 MYPN Ida Ertmanska changed review comment from: The association between MYPN and Hypertrophic cardiomyopathy was classified as Disputed in ClinGen (Hereditary Cardiovascular Disease GCEP, 2023).; to: The association between MYPN and Hypertrophic cardiomyopathy was classified as Disputed in ClinGen (Hereditary Cardiovascular Disease GCEP, 2023), due to the lack of genetic evidence, minimal experimental evidence, and no new evidence since the initial curation.
Hypertrophic cardiomyopathy v6.1 MYPN Ida Ertmanska commented on gene: MYPN
Childhood onset dystonia, chorea or related movement disorder v8.3 NTN1 Ida Ertmanska Classified gene: NTN1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v8.3 NTN1 Ida Ertmanska Added comment: Comment on list classification: There are 3 unrelated individuals reported in literature with heterozygous variants in NTN1 and congenital mirror movements. A knockout mouse model supports this gene disease association. Hence, this gene should be promoted to Green at the next update.
Childhood onset dystonia, chorea or related movement disorder v8.3 NTN1 Ida Ertmanska Gene: ntn1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v8.2 NTN1 Ida Ertmanska gene: NTN1 was added
gene: NTN1 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Q2_26_promote_green tags were added to gene: NTN1.
Mode of inheritance for gene: NTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NTN1 were set to 28945198; 33472083
Phenotypes for gene: NTN1 were set to Mirror movements 4, OMIM:618264; mirror movements 4, MONDO:0032641
Review for gene: NTN1 was set to GREEN
Added comment: PMID: 28945198 Meneret et al., 2017
NTN1 c.1801T>C/p.Cys601Arg variant of NTN1 segregated in a dominant manner with congenital mirror movements (CMM) in three affected members of a French family - though there were 2 asymptomatic carriers as well.
Heterozygous variant c.1552_1554del/p.Ile518del in NTN1 segregated with CMM in all 3 affected members of a family from the United Kingdom.
NTN1 variant c.1802G>C/p.Cys601Ser found in a sporadic case with CMM.

PMID: 33472083 Pourchet et al., 2021
Mouse model - a conditional ntn1 knockout in the brainstem impairs midline crossing of corticospinal axons and leads to mirror movements.
Sources: Literature
Mitochondrial disorders v10.4 MRPS23 Ida Ertmanska changed review comment from: Additional cases:
PMID: 41506652 Mandia et al., 2026
Male proband B:II:1 with variant in MRPS23 (NM_016070.4):c.119C>T, p.(Pro40Leu) - homozygous. Individual exhibited leukoencephalopathy with distinctive white matter abnormalities, intellectual impairment, sensorineural deafness, cerebellar ataxia, pyramidal syndrome, and amyotrophic weakness in distal limbs, attributed to distal motor neuropathy. Folinic acid treatment resulted in great improvement. Fibroblast analysis showed a decrease in expression of complex I and IV subunits.

PMID: 38086984 Ittiwut et al., 2023
Report of five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23 - all from Hmong hilltribe (Thailand) - likely founder variant, estimated to have occured 1550 yrs ago. The variant is found in 2 heterozygotes in gnomAD v4.1.1.
Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. 1 individual had severe hearing impairment. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV.; to: Additional cases:
PMID: 41506652 Mandia et al., 2026
Male proband B:II:1 with variant in MRPS23 (NM_016070.4):c.119C>T, p.(Pro40Leu) - homozygous. Individual exhibited leukoencephalopathy with distinctive white matter abnormalities, intellectual impairment, sensorineural deafness, cerebellar ataxia, pyramidal syndrome, and amyotrophic weakness in distal limbs, attributed to distal motor neuropathy. Folinic acid treatment resulted in great improvement. Fibroblast analysis showed a decrease in expression of complex I and IV subunits.

PMID: 38086984 Ittiwut et al., 2023
Report of five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23 - all from Hmong hilltribe (Thailand) - likely founder variant, estimated to have occured 1550 yrs ago. The variant is found in 2 heterozygotes in gnomAD v4.1.1.
Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. 1 individual had severe hearing impairment. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV.
Mitochondrial disorders v10.4 MRPS23 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MRPS23.
Mitochondrial disorders v10.4 MRPS23 Ida Ertmanska commented on gene: MRPS23: Comment on phenotypes: OMIM phenotype updated 14th May 2026.
Mitochondrial disorders v10.4 MRPS23 Ida Ertmanska Phenotypes for gene: MRPS23 were changed from hepatic disease and combined respiratory chain complex deficiencies to ?Combined oxidative phosphorylation deficiency 46, OMIM:618952; combined oxidative phosphorylation deficiency 46, MONDO:0033534
Mitochondrial disorders v10.3 MRPS23 Ida Ertmanska Publications for gene: MRPS23 were set to 26741492
Mitochondrial disorders v10.2 MRPS23 Ida Ertmanska Classified gene: MRPS23 as Amber List (moderate evidence)
Mitochondrial disorders v10.2 MRPS23 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic MRPS23 missense variants and a Combined oxidative phosphorylation deficiency (defects in CI and CIV shown in fibroblast cultures). Hence, this gene should be promoted to Green at the next GMS update.
Mitochondrial disorders v10.2 MRPS23 Ida Ertmanska Gene: mrps23 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v10.1 MRPS23 Ida Ertmanska reviewed gene: MRPS23: Rating: GREEN; Mode of pathogenicity: None; Publications: 38086984, 41506652; Phenotypes: ?Combined oxidative phosphorylation deficiency 46, OMIM:618952, combined oxidative phosphorylation deficiency 46, MONDO:0033534; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v9.4 MRPS23 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 14th May 2026.
Likely inborn error of metabolism v9.4 MRPS23 Ida Ertmanska Phenotypes for gene: MRPS23 were changed from hepatic disease and combined respiratory chain complex deficiencies to ?Combined oxidative phosphorylation deficiency 46, OMIM:618952; combined oxidative phosphorylation deficiency 46, MONDO:0033534
Likely inborn error of metabolism v9.3 MRPS23 Ida Ertmanska Publications for gene: MRPS23 were set to PMID: 26741492
Likely inborn error of metabolism v9.2 MRPS23 Ida Ertmanska Classified gene: MRPS23 as Amber List (moderate evidence)
Likely inborn error of metabolism v9.2 MRPS23 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic MRPS23 missense variants and a Combined oxidative phosphorylation deficiency (defects in CI and CIV shown in fibroblast cultures). Hence, this gene should be promoted to Green at the next GMS update.
Likely inborn error of metabolism v9.2 MRPS23 Ida Ertmanska Gene: mrps23 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v9.1 MRPS23 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MRPS23.
Possible mitochondrial disorder - nuclear genes v5.4 MRPS23 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MRPS23.
Likely inborn error of metabolism v9.1 MRPS23 Ida Ertmanska reviewed gene: MRPS23: Rating: GREEN; Mode of pathogenicity: None; Publications: 38086984, 41506652; Phenotypes: ?Combined oxidative phosphorylation deficiency 46, OMIM:618952, combined oxidative phosphorylation deficiency 46, MONDO:0033534; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v5.4 MRPS23 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 14th May 2026.
Possible mitochondrial disorder - nuclear genes v5.4 MRPS23 Ida Ertmanska Phenotypes for gene: MRPS23 were changed from Hepatic disease to Combined oxidative phosphorylation deficiency 46, OMIM:618952; combined oxidative phosphorylation deficiency 46, MONDO:0033534
Possible mitochondrial disorder - nuclear genes v5.3 MRPS23 Ida Ertmanska Publications for gene: MRPS23 were set to 26741492
Possible mitochondrial disorder - nuclear genes v5.2 MRPS23 Ida Ertmanska Classified gene: MRPS23 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v5.2 MRPS23 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic MRPS23 missense variants and a Combined oxidative phosphorylation deficiency (defects in CI and CIV shown in fibroblast cultures). Hence, this gene should be promoted to Green at the next GMS update.
Possible mitochondrial disorder - nuclear genes v5.2 MRPS23 Ida Ertmanska Gene: mrps23 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v5.1 MRPS23 Ida Ertmanska edited their review of gene: MRPS23: Changed publications to: 38086984, 41506652
Possible mitochondrial disorder - nuclear genes v5.1 MRPS23 Ida Ertmanska changed review comment from: Additional case:
PMID: 38086984 Ittiwut et al., 2023
Report of five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23 - all from Hmong hilltribe (Thailand) - likely founder variant, estimated to have occured 1550 yrs ago. The variant is found in 2 heterozygotes in gnomAD v4.1.1.
Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV.; to: Additional cases:
PMID: 41506652 Mandia et al., 2026
Male proband B:II:1 with variant in MRPS23 (NM_016070.4):c.119C>T, p.(Pro40Leu) - homozygous. Individual exhibited leukoencephalopathy with distinctive white matter abnormalities, intellectual impairment, sensorineural deafness, cerebellar ataxia, pyramidal syndrome, and amyotrophic weakness in distal limbs, attributed to distal motor neuropathy. Folinic acid treatment resulted in great improvement. Fibroblast analysis showed a decrease in expression of complex I and IV subunits.

PMID: 38086984 Ittiwut et al., 2023
Report of five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23 - all from Hmong hilltribe (Thailand) - likely founder variant, estimated to have occured 1550 yrs ago. The variant is found in 2 heterozygotes in gnomAD v4.1.1.
Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. 1 individual had severe hearing impairment. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV.
Possible mitochondrial disorder - nuclear genes v5.1 MRPS23 Ida Ertmanska reviewed gene: MRPS23: Rating: GREEN; Mode of pathogenicity: None; Publications: 38086984; Phenotypes: ?Combined oxidative phosphorylation deficiency 46, OMIM:618952, combined oxidative phosphorylation deficiency 46, MONDO:0033534; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v7.7 RNF2 Ida Ertmanska Classified gene: RNF2 as Amber List (moderate evidence)
Fetal anomalies v7.7 RNF2 Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with heterozygous variants (mostly de novo missense) and Luo-Schoch-Yamamoto syndrome. Prenatal complications were present in all 6 patients. Hence, this gene will be recommended for promotion to Green once PMID:40831499 is published.
Fetal anomalies v7.7 RNF2 Ida Ertmanska Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.16 RNF2 Ida Ertmanska Classified gene: RNF2 as Amber List (moderate evidence)
Intellectual disability v10.16 RNF2 Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with heterozygous variants (mostly de novo missense) and Luo-Schoch-Yamamoto syndrome. Syndromic GDD / ID was present in 5/6 patients. Hence, this gene will be recommended for promotion to Green once PMID:40831499 is published.
Intellectual disability v10.16 RNF2 Ida Ertmanska Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v7.6 RNF2 Ida Ertmanska gene: RNF2 was added
gene: RNF2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF2 were set to 33864376; 40831499
Phenotypes for gene: RNF2 were set to Luo-Schoch-Yamamoto syndrome, OMIM:619460; Luo-Schoch-Yamamoto syndrome, MONDO:0859171
Review for gene: RNF2 was set to GREEN
Added comment: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 4 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 3/4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (3/4), seizures (1/3), spasticity (2/4), developmental delay and intellectual disability (3/4).

PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles.
Sources: Literature
Intellectual disability v10.15 RNF2 Ida Ertmanska gene: RNF2 was added
gene: RNF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF2 were set to 33864376; 40831499
Phenotypes for gene: RNF2 were set to Luo-Schoch-Yamamoto syndrome, OMIM:619460; Luo-Schoch-Yamamoto syndrome, MONDO:0859171
Review for gene: RNF2 was set to GREEN
Added comment: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 4 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 3/4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (3/4), seizures (1/3), spasticity (2/4), developmental delay and intellectual disability (3/4).

PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles.
Sources: Literature
Early onset or syndromic epilepsy v9.5 RNF2 Ida Ertmanska changed review comment from: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 6 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (5/6), seizures (3/6), spasticity (2/6), developmental delay and intellectual disability (5/6), microcephaly (2/6).; to: PMID: 40831499 Ryan et al., 2025 - PRE-PRINT
identified 3 monoallelic RNF2 variants in 4 unrelated individuals: c.245G>T (p.S82I) (in 2 unrelated cases), c.796A>T (p.R266W), and c.472C>T (p.R158*). 3 cases were confirmed to be de novo. Patients were age 21 months - 7 yrs at examination. All 4 patients had prenatal complications (IUGR, oligohydramnios, polyhydramnios), gastrointestinal and feeding difficulties, and dysmorphic features. Cardiovascular anomalies detected in 3/4 individuals, 2 had hearing loss.
Neurological symptoms: hypotonia (3/4), seizures (1/3), spasticity (2/4), developmental delay and intellectual disability (3/4).
Early onset or syndromic epilepsy v9.5 RNF2 Ida Ertmanska Classified gene: RNF2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v9.5 RNF2 Ida Ertmanska Added comment: Comment on list classification: There are now 6 unrelated individuals reported in literature with heterozygous variants (mostly de novo missense) and Luo-Schoch-Yamamoto syndrome. Seizures were present in 3/6 patients. Hence, this gene will be recommended for promotion to Green once PMID:40831499 is published.
Early onset or syndromic epilepsy v9.5 RNF2 Ida Ertmanska Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v9.4 RNF2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 14th May 2026.
Early onset or syndromic epilepsy v9.4 RNF2 Ida Ertmanska Phenotypes for gene: RNF2 were changed from epilepsy; intellectual disability; intrauterine growth retardation to Luo-Schoch-Yamamoto syndrome, OMIM:619460; Luo-Schoch-Yamamoto syndrome, MONDO:0859171
Early onset or syndromic epilepsy v9.3 RNF2 Ida Ertmanska Publications for gene: RNF2 were set to 33864376
Early onset or syndromic epilepsy v9.2 RNF2 Ida Ertmanska Mode of inheritance for gene: RNF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v9.1 RNF2 Ida Ertmanska reviewed gene: RNF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40831499; Phenotypes: Luo-Schoch-Yamamoto syndrome, OMIM:619460, Luo-Schoch-Yamamoto syndrome, MONDO:0859171; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v9.3 VPS51 Ida Ertmanska Classified gene: VPS51 as Amber List (moderate evidence)
Severe microcephaly v9.3 VPS51 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated patients reported with biallelic VPS51 variants and severe syndromic ID / GDD. While severity was not stated, microcephaly was a consistent feature in all individuals. Hence, this gene can be promoted to Green at the next update.
Severe microcephaly v9.3 VPS51 Ida Ertmanska Gene: vps51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.14 VPS51 Ida Ertmanska changed review comment from: Additional cases:
PMID: 40565173 Aygun et al., 2025
2 sibs exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. Both homozygous for a c.1511C>T; p.Thr504Met VPS51 variant.

PMID: 40176246 Bhanudeep & Koneti, 2025
Proband: 15 month old boy with severe global developmental delay, failure to thrive, microcephaly, generalized hypotonia, nystagmus, Brisk DTRs. Neuroimaging showed diffuse hypomyelinated white matter, severely hypoplastic corpus callosum, and cerebral and cerebellar atrophy.; to: Additional cases:
PMID: 40565173 Aygun et al., 2025
2 sibs exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. Both homozygous for a c.1511C>T; p.Thr504Met VPS51 variant.

PMID: 40176246 Bhanudeep & Koneti, 2025
Proband: 15 month old boy with severe global developmental delay, failure to thrive, microcephaly, generalized hypotonia, nystagmus, Brisk DTRs. Neuroimaging showed diffuse hypomyelinated white matter, severely hypoplastic corpus callosum, and cerebral and cerebellar atrophy. WES revealed a homozygous VPS51 duplication p.Lys126_Met132dup.
Severe microcephaly v9.2 VPS51 Ida Ertmanska gene: VPS51 was added
gene: VPS51 was added to Severe microcephaly. Sources: Literature
Q2_26_promote_green tags were added to gene: VPS51.
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to 30624672; 31207318; 40176246; 40565173
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, OMIM:618606; pontocerebellar hypoplasia, type 13, MONDO:0032831; neurodevelopmental disorder, MONDO:0700092
Review for gene: VPS51 was set to GREEN
Added comment: PMID: 40565173 Aygun et al., 2025
2 sibs exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. Both homozygous for a c.1511C>T; p.Thr504Met VPS51 variant.

PMID: 40176246 Bhanudeep & Koneti, 2025
Proband: 15 month old boy with severe global developmental delay, failure to thrive, microcephaly, generalized hypotonia, nystagmus, Brisk DTRs. Neuroimaging showed diffuse hypomyelinated white matter, severely hypoplastic corpus callosum, and cerebral and cerebellar atrophy. WES revealed a homozygous VPS51 duplication p.Lys126_Met132dup.

PMID: 30624672 (2019) - 6-year-old girl with severe global developmental delay, pontocerebellar abnormalities, microcephaly, hypotonia, epilepsy and several systemic and peripheral dysfunctions. Exome sequencing revealed compound heterozygous variants in VPS51 ([c.2232delC; p.Asp745Thrfs*93];[c.1468C>T; p.Arg490Cys]). Functional studies of both variants indicate impaired function of the mutant protein.

PMID: 31207318 (2019) - two sisters with a homozygous three bp in-frame deletion (c.1419_1421del; p.Phe474del) in VPS51 associated with developmental delay, absent speech, severe ID and microcephaly. Development in both sisters was initially unremarkable; however, following an episode of fever (at 1 and 12 months of age, respectively), pyschomotor development was severely delayed. At 30 months and 9 years of age, respectively, neither sister had any language. No functional studies of the variant or patient cells were undertaken.
Sources: Literature
Intellectual disability v10.14 VPS51 Ida Ertmanska changed review comment from: Comment on list classification: There are now 4 unrelated patients reported with biallelic VPS51 variants and sever syndromic ID / GDD. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now 4 unrelated patients reported with biallelic VPS51 variants and severe syndromic ID / GDD. Hence, this gene can be promoted to Green at the next update.
Intellectual disability v10.14 VPS51 Ida Ertmanska Phenotypes for gene: VPS51 were changed from Pontocerebellar hypoplasia, type 13, MIM# 618606 to Pontocerebellar hypoplasia, type 13, OMIM:618606; pontocerebellar hypoplasia, type 13, MONDO:0032831; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v10.13 VPS51 Ida Ertmanska Publications for gene: VPS51 were set to 30624672; 31207318
Intellectual disability v10.12 VPS51 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: VPS51.
Intellectual disability v10.12 VPS51 Ida Ertmanska Classified gene: VPS51 as Amber List (moderate evidence)
Intellectual disability v10.12 VPS51 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated patients reported with biallelic VPS51 variants and sever syndromic ID / GDD. Hence, this gene can be promoted to Green at the next update.
Intellectual disability v10.12 VPS51 Ida Ertmanska Gene: vps51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.11 VPS51 Ida Ertmanska reviewed gene: VPS51: Rating: GREEN; Mode of pathogenicity: None; Publications: 40565173, 40176246; Phenotypes: Pontocerebellar hypoplasia, type 13, OMIM:618606, pontocerebellar hypoplasia, type 13, MONDO:0032831, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 RNF31 Ida Ertmanska Phenotypes for gene: RNF31 were changed from Bacterial infections, autoinflammation, amylopectinosis, lymphangiectasia; Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis; Polyglucosan body myopathy, early-onset, with or without immunodeficiency; autoinflammation and combined immunodeficiency; Combined immunodeficiencies with associated or syndromic features to Immunodeficiency 115 with autoinflammation, OMIM:620632; immunodeficiency 115 with autoinflammation, MONDO:0957981
Primary immunodeficiency or monogenic inflammatory bowel disease v9.8 RNF31 Ida Ertmanska Publications for gene: RNF31 were set to 30936877; 32086639; 26008899; 32048120
Autoinflammatory disorders v3.7 RNF31 Ida Ertmanska Classified gene: RNF31 as Amber List (moderate evidence)
Autoinflammatory disorders v3.7 RNF31 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals with biallelic RNF31 (HOIP) variants and primary immunodeficiency with autoinflammation. Hence, this gene can be promoted to Green at the next update.
Autoinflammatory disorders v3.7 RNF31 Ida Ertmanska Gene: rnf31 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.7 RNF31 Ida Ertmanska Classified gene: RNF31 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.7 RNF31 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals with biallelic RNF31 (HOIP) variants and primary immunodeficiency with autoinflammation. Hence, this gene can be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.7 RNF31 Ida Ertmanska Gene: rnf31 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 RNF31 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: RNF31.
Autoinflammatory disorders v3.6 RNF31 Ida Ertmanska gene: RNF31 was added
gene: RNF31 was added to Autoinflammatory disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: RNF31.
Mode of inheritance for gene: RNF31 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF31 were set to 26008899; 30936877; 39009172; 41026334
Phenotypes for gene: RNF31 were set to Immunodeficiency 115 with autoinflammation, OMIM:620632; immunodeficiency 115 with autoinflammation, MONDO:0957981
Review for gene: RNF31 was set to GREEN
Added comment: PMID: 41026334 L. Wang et al., 2025
Proband: 1-year-6-month-old Chinese boy with early-onset autoinflammation and immunodeficiency, leading to early death. He experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period. WES + Sanger detected comp het RNF31 variants: c.1654 C > T, p.Gln552Ter and c.3038 A > C, p.His1013Pro. Diagnosed with purulent meningitis, pneumonia, urinary tract infection, peritonitis, and growth retardation before 18 months of age. Immunophenotyping showed decrease in T cell frequency and total CD4 T cell counts.

PMID: 39009172 M. Wang et al., 2024
12yo Chinese male, homozygous for c.1883del, p.Gly628Alafs*52 in RNF31. He presented with infectious mononucleosis, necrotizing lymphadenitis, sepsis, primary peritonitis, lobar pneumonia, and recurrent viral and bacterial infections.
Functional: variant impairs MAPK signalling and sensitizes cells to TNF-induced cell death.

PMID: 30936877 Oda et al., 2019
8 year-old girl who presented with early-onset immune deficiency and autoinflammation. Noted to have eczematous dermatitis and chronic inflammation on skin biopsy. She had comp het variants in RNF31: c.1197G>C and c.1737+3A>G. RNA extracted from patient cells showed alternatively spliced transcripts not present in control cells

PMID: 26008899 Boisson et al., 2015
Female patient born to consanguineous parents of Kuwaiti descent; presented with multiorgan autoinflammation, systemic lymphangiectasia, weakness at lower extremities, subclinical amylopectinosis, and a combined immunodeficiency manifesting as chronic diarrhea and recurrent viral and bacterial infections, associated with lymphopenia, antibody deficiency and an impaired distribution and function of T lymphocytes. She was homozygous for c.215T>C, p.Leu72Pro in RNF31.

The association between RNF31 and AR immunodeficiency 115 with autoinflammation was classified as Moderate in ClinGen (SCID-CID GCEP, 2025).
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 RNF31 Ida Ertmanska changed review comment from: PMID: 41026334 L. Wang et al., 2025
Proband: 1-year-6-month-old Chinese boy with early-onset autoinflammation and immunodeficiency, leading to early death. He experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period. WES + Sanger detected comp het RNF31 variants: c.1654 C > T, p.Gln552Ter and c.3038 A > C, p.His1013Pro. Diagnosed with purulent meningitis, pneumonia, urinary tract infection, peritonitis, and growth retardation before 18 months of age. Immunophenotyping showed decrease in T cell frequency and total CD4 T cell counts.

PMID: 39009172 M. Wang et al., 2024
12yo Chinese male, homozygous for c.1883del, p.Gly628Alafs*52 in RNF31. He presented with infectious mononucleosis, necrotizing lymphadenitis, sepsis, primary peritonitis, lobar pneumonia, and recurrent viral and bacterial infections.
Functional: variant impairs MAPK signalling and sensitizes cells to TNF-induced cell death.

PMID: 30936877 Oda et al., 2019
8 year-old girl who presented with early-onset immune deficiency and autoinflammation. Noted to have eczematous dermatitis and chronic inflammation on skin biopsy. She had comp het variants in RNF31: c.1197G>C and c.1737+3A>G. RNA extracted from patient cells showed alternatively spliced transcripts not present in control cells

PMID: 26008899 Boisson et al., 2015
Female patient born to consanguineous parents of Kuwaiti descent; presented with multiorgan autoinflammation, systemic lymphangiectasia, weakness at lower extremities, subclinical amylopectinosis, and a combined immunodeficiency manifesting as chronic diarrhea and recurrent viral and bacterial infections, associated with lymphopenia, antibody deficiency and an impaired distribution and function of T lymphocytes.
She was homozygous for c.215T>C, p.Leu72Pro in RNF31; to: PMID: 41026334 L. Wang et al., 2025
Proband: 1-year-6-month-old Chinese boy with early-onset autoinflammation and immunodeficiency, leading to early death. He experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period. WES + Sanger detected comp het RNF31 variants: c.1654 C > T, p.Gln552Ter and c.3038 A > C, p.His1013Pro. Diagnosed with purulent meningitis, pneumonia, urinary tract infection, peritonitis, and growth retardation before 18 months of age. Immunophenotyping showed decrease in T cell frequency and total CD4 T cell counts.

PMID: 39009172 M. Wang et al., 2024
12yo Chinese male, homozygous for c.1883del, p.Gly628Alafs*52 in RNF31. He presented with infectious mononucleosis, necrotizing lymphadenitis, sepsis, primary peritonitis, lobar pneumonia, and recurrent viral and bacterial infections.
Functional: variant impairs MAPK signalling and sensitizes cells to TNF-induced cell death.

PMID: 30936877 Oda et al., 2019
8 year-old girl who presented with early-onset immune deficiency and autoinflammation. Noted to have eczematous dermatitis and chronic inflammation on skin biopsy. She had comp het variants in RNF31: c.1197G>C and c.1737+3A>G. RNA extracted from patient cells showed alternatively spliced transcripts not present in control cells

PMID: 26008899 Boisson et al., 2015
Female patient born to consanguineous parents of Kuwaiti descent; presented with multiorgan autoinflammation, systemic lymphangiectasia, weakness at lower extremities, subclinical amylopectinosis, and a combined immunodeficiency manifesting as chronic diarrhea and recurrent viral and bacterial infections, associated with lymphopenia, antibody deficiency and an impaired distribution and function of T lymphocytes. She was homozygous for c.215T>C, p.Leu72Pro in RNF31.

The association between RNF31 and AR immunodeficiency 115 with autoinflammation was classified as Moderate in ClinGen (SCID-CID GCEP, 2025).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 RNF31 Ida Ertmanska reviewed gene: RNF31: Rating: GREEN; Mode of pathogenicity: None; Publications: 26008899, 30936877, 39009172, 41026334; Phenotypes: Immunodeficiency 115 with autoinflammation, OMIM:620632, immunodeficiency 115 with autoinflammation, MONDO:0957981; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v5.4 TXNRD2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th May 2026.
Congenital adrenal hypoplasia v5.4 TXNRD2 Ida Ertmanska Phenotypes for gene: TXNRD2 were changed from Familial glucocorticoid deficiency to ?Glucocorticoid deficiency 5 , OMIM:617825; glucocorticoid deficiency 5, MONDO:0040502
Congenital adrenal hypoplasia v5.3 TXNRD2 Ida Ertmanska Publications for gene: TXNRD2 were set to PMC4207928; 24601690
Congenital adrenal hypoplasia v5.2 TXNRD2 Ida Ertmanska Classified gene: TXNRD2 as Amber List (moderate evidence)
Congenital adrenal hypoplasia v5.2 TXNRD2 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals reported with biallelic TXNRD2 variants and Glucocorticoid deficiency, evidenced by loss of cortisol production and severe elevation of ACTH. Hence, this gene should be promoted to Green at the next update.
Congenital adrenal hypoplasia v5.2 TXNRD2 Ida Ertmanska Gene: txnrd2 has been classified as Amber List (Moderate Evidence).
Congenital adrenal hypoplasia v5.1 TXNRD2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TXNRD2.
Congenital adrenal hypoplasia v5.1 TXNRD2 Ida Ertmanska reviewed gene: TXNRD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24601690, 30237576, 38011841, 39097530, 40726908; Phenotypes: ?Glucocorticoid deficiency 5 , OMIM:617825, glucocorticoid deficiency 5, MONDO:0040502; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Short QT syndrome v3.22 SLC4A3 Ida Ertmanska Publications for gene: SLC4A3 were set to 29167417; 29697308; 36806574; 18382206; 19862833; 30420954
Short QT syndrome v3.21 SLC4A3 Ida Ertmanska edited their review of gene: SLC4A3: Changed publications to: 36806574, 41039816
Short QT syndrome v3.21 SLC4A3 Ida Ertmanska changed review comment from: PMID: 36806574 Christiansen et al., 2023
Identified 4 patients with SQTS, heterozygous for novel nonsynonymous SLC4A3 variants: p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His, and 1 patient with the known p.Arg370His variant.
Functional: Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals. This was rescued by the WT human SLC4A3 protein expression, but not by the mutant proteins.

The relationship between SLC4A3 and Short QT syndrome was classified as Moderate in ClinGen (Short QT Syndrome GCEP, 2020).; to: PMID: 41039816 Crea et al., 2025
A novel heterozygous SLC4A3 mutation (c.1157G>T; p.Gly386Val) was identified in the proband and her mother, both with short QT intervals. The family history included multiple cases of sudden unexplained death and epilepsy

PMID: 36806574 Christiansen et al., 2023
Identified 4 patients with SQTS, heterozygous for novel nonsynonymous SLC4A3 variants: p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His, and 1 patient with the known p.Arg370His variant.
Functional: Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals. This was rescued by the WT human SLC4A3 protein expression, but not by the mutant proteins.

The relationship between SLC4A3 and Short QT syndrome was classified as Moderate in ClinGen (Short QT Syndrome GCEP, 2020).
Short QT syndrome v3.21 SLC4A3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 13th May 2026.
Short QT syndrome v3.21 SLC4A3 Ida Ertmanska Phenotypes for gene: SLC4A3 were changed from short QT; ventricular fibrillation; cardiac arrest to Short QT syndrome 7, OMIM:620231; short QT syndrome 7, MONDO:0859368
Short QT syndrome v3.20 SLC4A3 Ida Ertmanska Publications for gene: SLC4A3 were set to 29167417; 29697308
Short QT syndrome v3.19 SLC4A3 Ida Ertmanska Mode of inheritance for gene: SLC4A3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Short QT syndrome v3.18 SLC4A3 Ida Ertmanska Classified gene: SLC4A3 as Amber List (moderate evidence)
Short QT syndrome v3.18 SLC4A3 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated patients with heterozygous SLC4A3 variants and short QT syndrome. Christiansen et al. (PMID: 36806574, 2023) pose that variants in SLC4A3 represent the most common cause of SQTS. Hence, this gene should be promoted to Green at the next update.
Short QT syndrome v3.18 SLC4A3 Ida Ertmanska Gene: slc4a3 has been classified as Amber List (Moderate Evidence).
Short QT syndrome v3.17 SLC4A3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: SLC4A3.
Short QT syndrome v3.17 SLC4A3 Ida Ertmanska reviewed gene: SLC4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36806574; Phenotypes: Short QT syndrome 7, OMIM:620231, short QT syndrome 7, MONDO:0859368; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v4.14 TUBA8 Achchuthan Shanmugasundram Classified gene: TUBA8 as Amber List (moderate evidence)
Bleeding and platelet disorders v4.14 TUBA8 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Carl Fratter, PMID:34662886 (2021) reported UK Biobank cohort study, of which one variant was reported in TUBA8 gene as associated with increased platelet distribution width (but no association reported with platelet count).

PMID:34704371 (2022) reported the identification of six distinct heterozygous variants in six unrelated individuals from a large cohort of French blood donors with mild thrombocytopenia. The individuals were generally asymptomatic and one had menorrhagia. There is also some functional data.

As these reported individuals are from large cohorts and they are mostly asymptomatic, this can only be rated amber with current evidence.
Bleeding and platelet disorders v4.14 TUBA8 Achchuthan Shanmugasundram Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.9 TBX2 Ida Ertmanska Classified gene: TBX2 as Amber List (moderate evidence)
Skeletal dysplasia v9.9 TBX2 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated individuals reported with heterozygous TBX2 variants and skeletal malformations - a proband with severe chondrodysplasia punctata, a family with dominant osteochondrodysplasia, a patient with congenital fusions of the thoracic spine and hemivertebrae with scoliosis, and another individual rib fusions and scoliosis. Hence, this gene can now be promoted to Green on Skeletal dysplasia.
Skeletal dysplasia v9.9 TBX2 Ida Ertmanska Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v4.13 TUBA8 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: OMIM phenotype last accessed on 13 May 2026; to: Comment on phenotypes: OMIM phenotype last accessed on 13 May 2026.
Bleeding and platelet disorders v4.13 TUBA8 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 13 May 2026
Bleeding and platelet disorders v4.13 TUBA8 Achchuthan Shanmugasundram Phenotypes for gene: TUBA8 were changed from to Macrothrombocytopenia, isolated, 2, autosomal dominant, OMIM:619840; macrothrombocytopenia, isolated, 2, autosomal dominant, MONDO:0030827
Bleeding and platelet disorders v4.12 TUBA8 Achchuthan Shanmugasundram Publications for gene: TUBA8 were set to PMID: 34662886)
Bleeding and platelet disorders v4.11 TUBA8 Achchuthan Shanmugasundram reviewed gene: TUBA8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Macrothrombocytopenia, isolated, 2, autosomal dominant, OMIM:619840, macrothrombocytopenia, isolated, 2, autosomal dominant, MONDO:0030827; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v9.8 TBX2 Ida Ertmanska gene: TBX2 was added
gene: TBX2 was added to Skeletal dysplasia. Sources: Literature
Q2_26_promote_green tags were added to gene: TBX2.
Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX2 were set to 29726930; 35311234; 36733940
Phenotypes for gene: TBX2 were set to Vertebral anomalies and variable endocrine and T-cell dysfunction, OMIM:618223; vertebral anomalies and variable endocrine and T-cell dysfunction, MONDO:0032607; chondrodysplasia, MONDO:0022723
Review for gene: TBX2 was set to GREEN
Added comment: PMID: 36733940 Rafeeq et al., 2023
Patient (5yo female from Pakistan) with severe chondrodysplasia punctata with developmental delay, deceased at 5yrs. WES detected a de novo heterozygous c.529A>T; p.Lys177* variant in TBX2. MRI and radiographs showed platybasia at the skull base, delayed myelination for the patient’s age, and severe skeletal deformities. No hearing loss.

PMID: 35311234 Makitie et al., 2022
Report of a three-generation Finnish family with an unusual, autosomal dominant form of osteochondrodysplasia and an empty sella. Affected individuals (age range 24-44 years) exhibit codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities. Joint pain, obesity, and dysmorphic features were also noted. WES detected heterozygous c.899C>T (p.Thr300Met) variant in TBX2. Proband's father, and grandfather were similarly affected, deceased in their 40s - only proband and unaffected family members were sequenced. Clinical diagnosis of osteochondrodysplasia and osteoarthritis. No hearing loss or impaired cognition.

PMID: 29726930 Liu et al., 2018
Four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies (PDA, double outlet right ventricle), skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome. All 4 are heterozygotes for TBX2 variants: p.R20Q variant is shared by three affected family members - segregated in autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Skeletal features: congenital fusions of the thoracic spine and hemivertebrae with scoliosis (P4), rib fusions, scoliosis (P1), campodactyly (P1-3).
Sources: Literature
Bleeding and platelet disorders v4.11 TUBA4A Achchuthan Shanmugasundram Classified gene: TUBA4A as Amber List (moderate evidence)
Bleeding and platelet disorders v4.11 TUBA4A Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Carl Fratter, there is only one published human case of macrothrombocytopenia and functional evidence from mouse model reported in association with variants in TUBA4A gene. This gene has been classified with 'Limited' rating by the Hemostasis Thrombosis expert panel in ClinGen. This gene can therefore be rated amber with the current evidence.
Bleeding and platelet disorders v4.11 TUBA4A Achchuthan Shanmugasundram Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v4.10 TUBA4A Achchuthan Shanmugasundram Publications for gene: TUBA4A were set to PMID: 30760556; 36026602
Corneal dystrophy v4.9 MAB21L1 Achchuthan Shanmugasundram Classified gene: MAB21L1 as Amber List (moderate evidence)
Corneal dystrophy v4.9 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 11 patients from six unrelated families reported with bilateral corneal opacities/ corneal dystrophy and with biallelic MAB21L1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Corneal dystrophy v4.9 MAB21L1 Achchuthan Shanmugasundram Gene: mab21l1 has been classified as Amber List (Moderate Evidence).
Corneal dystrophy v4.8 MAB21L1 Achchuthan Shanmugasundram gene: MAB21L1 was added
gene: MAB21L1 was added to Corneal dystrophy. Sources: Literature
Q2_26_promote_green tags were added to gene: MAB21L1.
Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAB21L1 were set to 27103078; 30487245
Phenotypes for gene: MAB21L1 were set to Cerebellar, ocular, craniofacial, and genital syndrome, OMIM:618479; cerebellar, ocular, craniofacial, and genital syndrome, MONDO:0032774
Review for gene: MAB21L1 was set to GREEN
Added comment: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from five consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

Biallelic variants in this gene are associated with relevant phenotypes in OMIM (MIM #618479, last accessed 12 May 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and ClinGen (Strong rating by Syndromic disorders Expert panel - https://search.clinicalgenome.org/CCID:008388).
Sources: Literature
Albinism or congenital nystagmus v4.8 MAB21L1 Achchuthan Shanmugasundram Classified gene: MAB21L1 as Amber List (moderate evidence)
Albinism or congenital nystagmus v4.8 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are 10 patients from five unrelated families reported with horizontal nystagmus and with biallelic MAB21L1 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Albinism or congenital nystagmus v4.8 MAB21L1 Achchuthan Shanmugasundram Gene: mab21l1 has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v4.7 MAB21L1 Achchuthan Shanmugasundram gene: MAB21L1 was added
gene: MAB21L1 was added to Albinism or congenital nystagmus. Sources: Literature
Q2_26_promote_green tags were added to gene: MAB21L1.
Mode of inheritance for gene: MAB21L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAB21L1 were set to 27103078; 30487245
Phenotypes for gene: MAB21L1 were set to Cerebellar, ocular, craniofacial, and genital syndrome, OMIM:618479; cerebellar, ocular, craniofacial, and genital syndrome, MONDO:0032774
Review for gene: MAB21L1 was set to GREEN
Added comment: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from five consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

Biallelic variants in this gene are associated with relevant phenotypes in OMIM (MIM #618479, last accessed 12 May 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and ClinGen (Strong rating by Syndromic disorders Expert panel - https://search.clinicalgenome.org/CCID:008388).
Sources: Literature
Intellectual disability v10.11 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 12 May 2026.
Intellectual disability v10.11 MAB21L1 Achchuthan Shanmugasundram Phenotypes for gene: MAB21L1 were changed from Global developmental delay; Intellectual disability; Cerebellar hypoplasia; Abnormality of the eye; Abnormality of the genital system; No OMIM number to Cerebellar, ocular, craniofacial, and genital syndrome OMIM:618479
Structural eye disease v5.5 MAB21L1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MAB21L1.
Structural eye disease v5.5 MAB21L1 Achchuthan Shanmugasundram Classified gene: MAB21L1 as Amber List (moderate evidence)
Structural eye disease v5.5 MAB21L1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Biallelic variants in MAB21L1 are associated with a syndromic phenotype including ophthalmological presentations such as horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration. These phenotypes are not relevant for this panel.

However, there is sufficient evidence available for the association of monoallelic MAB21L1 variants with phenotypes relevant to this panel such as microphthalmia and aniridia. Hence, this gene should be promoted to green rating with MOI set as 'MONOALLELIC' in the next GMS update.
Structural eye disease v5.5 MAB21L1 Achchuthan Shanmugasundram Gene: mab21l1 has been classified as Amber List (Moderate Evidence).
Structural eye disease v5.4 MAB21L1 Achchuthan Shanmugasundram Phenotypes for gene: MAB21L1 were changed from to microphthalmia, MONDO:0021129; aniridia, MONDO:0019172
Structural eye disease v5.3 MAB21L1 Achchuthan Shanmugasundram Publications for gene: MAB21L1 were set to 33973683; 36413568; 36446583; 36892533; 39016008
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram edited their review of gene: MAB21L1: Changed phenotypes to: microphthalmia, MONDO:0021129, aniridia, MONDO:0019172
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram changed review comment from: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature; to: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.

Only biallelic variants in this gene are associated with relevant phenotypes in OMIM (MIM #618479, last accessed 12 May 2026), Gene2Phenotype (with 'definitive' rating on the DD and Eye panels) and ClinGen (Strong rating by Syndromic disorders Expert panel - https://search.clinicalgenome.org/CCID:008388). However, only monoallelic variants are associated with phenotypes relevant to this panel.
Sources: Literature
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram edited their review of gene: MAB21L1: Changed publications to: 27103078, 30487245, 33973683, 36413568, 36446583, 36892533, 39016008
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram changed review comment from: PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature; to: PMID:27103078 (2017) reported the identification of a homozygous frameshift variant in MAB21L1 gene (p.Cys246Leufs*18) in a boy with scrotum agensis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global developmental delay. Ocular anomalies included nystagmus, convergent strabismus and corneal dystrophy. There is also functional evidence available from knockout mice which presented a similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia.

PMID:30487245 (2019) reported the identification of four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Ocular features included horizontal nystagmus, bilateral corneal opacities/ corneal dystrophy, strabismus and retinal degeneration.

PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram edited their review of gene: MAB21L1: Changed publications to: 30487245, 33973683, 36413568, 36446583, 36892533, 39016008
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram changed review comment from: PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature; to: PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature
Structural eye disease v5.2 MAB21L1 Achchuthan Shanmugasundram gene: MAB21L1 was added
gene: MAB21L1 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: MAB21L1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAB21L1 were set to 33973683; 36413568; 36446583; 36892533; 39016008
Review for gene: MAB21L1 was set to GREEN
Added comment: PMID:33973683 (2021) reported a heterozygous novel variant in MAB21L1 gene (c.152G>T/ p.Arg51Leu), in two family members with microphthalmia and aniridia, as well as novel or rare compound heterozygous variants of uncertain significance (c.184C>T/ p.Arg62Cys; c.-68T>C and c.658G>C/ p.Gly220Arg; c.*529A>G) in two additional probands with microphthalmia, coloboma and/or cataracts. There is also function evidence available from in vitro studies of coding variants and in vivo complementation assays using the zebrafish mab21l2 Q48Sfs*5 loss-of-function line.

PMID:36413568 (2022) reported nine patients from five families with severe aniridia and/or microphthalmia with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. The detected variants are c.152G>A/ p.Arg51Gln, c.152G>T/ p.Arg51Leu, c.152G>C/ p.Arg51Pro and c.155T>G/ p.Phe52Cys. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes.

PMID:36446583 (2023) reported the identification of a novel missense variant (p.Phe52Leu) in a three-generation pedigree with autosomal dominant microphthalmia.

PMID:36892533 (2023) reported the identification of three heterozygous missense variants in MAB21L1 gene in five unrelated families, including c.152G>T/ p.Arg51Leu in two, c.152G>A/ p.Arg51Gln in two, and c.155T>G/ p.Phe52Cys in one. All patients presented with similar blepharophimosis plus anterior segment and macular dysgenesis (BAMD) phenotype.

PMID:39016008 (2024) reported an additional family with four individuals diagnosed with microphthalmia and with Arg51 variant in MAB21L1 gene.
Sources: Literature
Paediatric disorders - additional genes v8.6 PRDM6 Ida Ertmanska Publications for gene: PRDM6 were set to
Paediatric disorders - additional genes v8.5 PRDM6 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 12 May 2026.
Paediatric disorders - additional genes v8.5 PRDM6 Ida Ertmanska Phenotypes for gene: PRDM6 were changed from Patent ductus arteriosus 3 to Patent ductus arteriosus 3, OMIM:617039; patent ductus arteriosus 3, MONDO:0024266
Paediatric disorders - additional genes v8.4 PRDM6 Ida Ertmanska Mode of inheritance for gene: PRDM6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v8.3 PRDM6 Ida Ertmanska Classified gene: PRDM6 as Amber List (moderate evidence)
Paediatric disorders - additional genes v8.3 PRDM6 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated families with heterozygous PRDM6 variants and isolated patent ductus arteriosus. Hence, this gene should be promoted to Green at the next update.
Paediatric disorders - additional genes v8.3 PRDM6 Ida Ertmanska Gene: prdm6 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.2 PRDM6 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: PRDM6.
Paediatric disorders - additional genes v8.2 PRDM6 Ida Ertmanska reviewed gene: PRDM6: Rating: GREEN; Mode of pathogenicity: None; Publications: 27181681, 38071433; Phenotypes: Patent ductus arteriosus 3, OMIM:617039, patent ductus arteriosus 3, MONDO:0024266; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v3.5 PLCG1 Ida Ertmanska Classified gene: PLCG1 as Amber List (moderate evidence)
Autoinflammatory disorders v3.5 PLCG1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with heterozygous PLCG1 variants and an immune dysregulation disorder, including variable autoimmune feature. Hence, this gene should be promoted to Green at the next update.
Autoinflammatory disorders v3.5 PLCG1 Ida Ertmanska Gene: plcg1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.10 PLCG1 Ida Ertmanska Phenotypes for gene: PLCG1 were changed from ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790 to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790; hearing loss disorder, MONDO:0005365
Monogenic hearing loss v6.9 PLCG1 Ida Ertmanska Phenotypes for gene: PLCG1 were changed from hearing impairment; ophthalmologic abnormalities; cardiac septal defects to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790
Monogenic hearing loss v6.8 PLCG1 Ida Ertmanska Publications for gene: PLCG1 were set to 38260438
Monogenic hearing loss v6.7 PLCG1 Ida Ertmanska Tag watchlist was removed from gene: PLCG1.
Tag Q2_26_promote_green tag was added to gene: PLCG1.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 PLCG1 Ida Ertmanska Classified gene: PLCG1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 PLCG1 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated individuals with heterozygous PLCG1 variants and an immune dysregulation disorder, including recurrent infections due to immunological deficiencies. Hence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.6 PLCG1 Ida Ertmanska Gene: plcg1 has been classified as Amber List (Moderate Evidence).
Autoinflammatory disorders v3.4 PLCG1 Ida Ertmanska gene: PLCG1 was added
gene: PLCG1 was added to Autoinflammatory disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: PLCG1.
Mode of inheritance for gene: PLCG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLCG1 were set to 37422272; 40862571
Phenotypes for gene: PLCG1 were set to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790
Review for gene: PLCG1 was set to GREEN
Added comment: PMID: 40862571 Ma et al., 2025 (based on pre-print mentioned in previous reviews)
Report of seven individuals from 4 unrelated families with heterozygous missense variants in PLCG1: 3 individuals with de novo het variants: c.3056A>G, p.(Asp1019Gly)], [c.1139A>G, p.(His380Arg)] and [c.3494A>G, p.(Asp1165Gly)]. Individuals 4–7 are from the same family, and all carry the PLCG1 variant [c.1789C>T p.(Leu597Phe)].
Phenotypic spectrum: hearing loss (5/7, mild to profound), cardiac septal defects (3/6), and other less specific syndromic findings. Abnormal brain MRI findings in 2/3 assessed. Various immunological issues included:
P3: T lymphocytopenia, recurrent pulmonary infections;
P4: joint inflammation, tarsal synovitis, recurrent respiratory and lung infections, as well as inflammatory lymphadenopathy;
P5: immune thrombocytopenic purpura, polyarthritis, autoimmune pulmonary fibrosis, pneumococcal sepsis with chronic thrombocytopenia and IgA and IgG2 deficiency;
P6: history of recurrent upper respiratory and lung infections due to a mild IgA and IgG2 deficiency;

PMID: 37422272 Tao et al., 2024
7yo female patient with a de novo p.S1021F variant in PLCG1 and early-onset immune dysregulation disease: recurrent skin ecchymosis, epistaxis and gingival bleeding, lymphadenopathy. No mention of hearing loss.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v9.5 PLCG1 Ida Ertmanska gene: PLCG1 was added
gene: PLCG1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Q2_26_promote_green tags were added to gene: PLCG1.
Mode of inheritance for gene: PLCG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLCG1 were set to 37422272; 40862571
Phenotypes for gene: PLCG1 were set to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790
Review for gene: PLCG1 was set to GREEN
Added comment: PMID: 40862571 Ma et al., 2025 (based on pre-print mentioned in previous reviews)
Report of seven individuals from 4 unrelated families with heterozygous missense variants in PLCG1: 3 individuals with de novo het variants: c.3056A>G, p.(Asp1019Gly)], [c.1139A>G, p.(His380Arg)] and [c.3494A>G, p.(Asp1165Gly)]. Individuals 4–7 are from the same family, and all carry the PLCG1 variant [c.1789C>T p.(Leu597Phe)].
Phenotypic spectrum: hearing loss (5/7, mild to profound), cardiac septal defects (3/6), and other less specific syndromic findings. Abnormal brain MRI findings in 2/3 assessed. Various immunological issues included:
P3: T lymphocytopenia, recurrent pulmonary infections;
P4: joint inflammation, tarsal synovitis, recurrent respiratory and lung infections, as well as inflammatory lymphadenopathy;
P5: immune thrombocytopenic purpura, polyarthritis, autoimmune pulmonary fibrosis, pneumococcal sepsis with chronic thrombocytopenia and IgA and IgG2 deficiency;
P6: history of recurrent upper respiratory and lung infections due to a mild IgA and IgG2 deficiency;

PMID: 37422272 Tao et al., 2024
7yo female patient with a de novo p.S1021F variant in PLCG1 and early-onset immune dysregulation disease: recurrent skin ecchymosis, epistaxis and gingival bleeding, lymphadenopathy. No mention of hearing loss.
Sources: Literature
Monogenic hearing loss v6.7 PLCG1 Ida Ertmanska reviewed gene: PLCG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37422272, 40862571; Phenotypes: ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska changed review comment from: New HGNC approved gene symbol for MKL1 is MRTFA; to: New HGNC approved gene symbol for MKL1 is MRTFA; new-gene-name tag was added.
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska commented on gene: MKL1: New HGNC approved gene symbol for MKL1 is MRTFA
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska Classified gene: MKL1 as Red List (low evidence)
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska Added comment: Comment on list classification: As only one case with biallelic MKL1 variants presented with broad autoinflammation symptoms, this gene can only be rated Red with current evidence.
Autoinflammatory disorders v3.3 MKL1 Ida Ertmanska Gene: mkl1 has been classified as Red List (Low Evidence).
Autoinflammatory disorders v3.2 MKL1 Ida Ertmanska changed review comment from: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Sources: Literature; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, erythematous rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. Inflammatory bowel disease was suspected. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Sources: Literature
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska changed review comment from: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Autoinflammatory disorders v3.2 MKL1 Ida Ertmanska gene: MKL1 was added
gene: MKL1 was added to Autoinflammatory disorders. Sources: Literature
new-gene-name tags were added to gene: MKL1.
Mode of inheritance for gene: MKL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MKL1 were set to 26224645; 27479822; 32128589; 40808667
Phenotypes for gene: MKL1 were set to ?Immunodeficiency 66 , OMIM:618847; immunodeficiency 66, MONDO:0030013; neutropenia, MONDO:0001475
Review for gene: MKL1 was set to RED
Added comment: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Sources: Literature
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska changed review comment from: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L).

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L). Not sure on zygosity of this patient.

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska edited their review of gene: MKL1: Changed publications to: 26224645, 27479822, 32128589, 40808667
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska Classified gene: MKL1 as Amber List (moderate evidence)
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska Added comment: Comment on list classification: There are at least 3 unrelated individuals reported in literature with biallelic MKL1 variants associated with immunodeficiency as well thrombocytopenia, neutropenia, and lymphopenia. Hence, this gene should be promoted to Green at the next update.
Bleeding and platelet disorders v4.9 MKL1 Ida Ertmanska Gene: mkl1 has been classified as Amber List (Moderate Evidence).
Bleeding and platelet disorders v4.8 MKL1 Ida Ertmanska changed review comment from: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 26224645 Record et al., 2015
Patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. He was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 27479822 Johnson et al., 2016
Patient F37.I reported to harbour variant c.1723G>A, p.Val575Met in MKL1 (classed as VUS). The patient has a mild reduction in platelet count (130×109/L).

PMID: 26224645 Record et al., 2015
Female patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. Parents are second cousins. She was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Bleeding and platelet disorders v4.8 MKL1 Ida Ertmanska Publications for gene: MKL1 were set to 27479822
Bleeding and platelet disorders v4.7 MKL1 Ida Ertmanska Mode of inheritance for gene: MKL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v4.6 MKL1 Ida Ertmanska changed review comment from: 3rd case:
PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

PMID: 32128589 Sprenkeler et al. 2020
2 sibs with severe early-onset immunodeficiency, lymphopenia and thrombocytopenia. WES revealed homozygous MKL1 variant NM_020831.4:c.1356dup (p.(Val453Argfs*16). 1st sib died from infection in the first weeks of life; younger sister had milder phenotype as she underwent hematopoietic stem cell transplantation at 9 weeks.

PMID: 26224645 Record et al., 2015
Patient with immunodeficiency with recurring severe bacterial infections and mild thrombocytopenia. He was homozygous for p.K723X variant in MKL1. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Bleeding and platelet disorders v4.6 MKL1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MKL1.
Bleeding and platelet disorders v4.6 MKL1 Ida Ertmanska reviewed gene: MKL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26224645, 32128589, 40808667; Phenotypes: ?Immunodeficiency 66 , OMIM:618847, immunodeficiency 66, MONDO:0030013, neutropenia, MONDO:0001475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.4 MKL1 Ida Ertmanska changed review comment from: 3rd case:
PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA).

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: 3rd case:
PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA). Multiple neutrophil defects demonstrated in patient cells, including increased apoptosis and decreased migration ability.

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.4 MKL1 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutrophil motility defects. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutrophil defects. Hence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.4 MKL1 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutropenia and neutrophil motility defects. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutrophil motility defects. Hence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.4 MKL1 Ida Ertmanska Phenotypes for gene: MKL1 were changed from ?Immunodeficiency 66 , OMIM:618847; neutropenia, MONDO:0001475 to ?Immunodeficiency 66 , OMIM:618847; immunodeficiency 66, MONDO:0030013; neutropenia, MONDO:0001475
Primary immunodeficiency or monogenic inflammatory bowel disease v9.3 MKL1 Ida Ertmanska Phenotypes for gene: MKL1 were changed from Susceptibility to severe bacterial infection; Mild thrombocytopenia; Congenital defects of phagocyte number or function to ?Immunodeficiency 66 , OMIM:618847; neutropenia, MONDO:0001475
Primary immunodeficiency or monogenic inflammatory bowel disease v9.2 MKL1 Ida Ertmanska Classified gene: MKL1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.2 MKL1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with biallelic MKL1 variants and immunodeficiency due to neutropenia and neutrophil motility defects. Hence, this gene should be promoted to Green at the next update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.2 MKL1 Ida Ertmanska Gene: mkl1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 MKL1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: MKL1.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 MKL1 Ida Ertmanska changed review comment from: 3rd case:
PMID: 40808667 Li et al., 2025
Patient presented with early-onset infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA).

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).; to: 3rd case:
PMID: 40808667 Li et al., 2025
Report of a 3yo girl from China, non-consanguineous parents. Patient presented with early-onset bacterial infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. WES detected comp het variants p.Q377X & p.C684X in MKL1 (MRTFA).

MRTFA is putatively associated with AR ?Immunodeficiency 66, OMIM:618847 in OMIM (accessed 12th May 2026).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 MKL1 Ida Ertmanska reviewed gene: MKL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40808667; Phenotypes: ?Immunodeficiency 66 , OMIM:618847; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.7 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Skeletal dysplasia v9.7 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome. Skeletal findings included mild spondylo-epi-metaphyseal dysplasia in 1 case, and shortening of metacarpals and metatarsals in 3 sisters. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including skeletal dysplasia. As the skeletal findings are relatively mild, this gene should remain Amber on Skeletal dysplasia.
Skeletal dysplasia v9.7 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.6 LOXL3 Ida Ertmanska Publications for gene: LOXL3 were set to 25663169
Skeletal dysplasia v9.5 LOXL3 Ida Ertmanska Phenotypes for gene: LOXL3 were changed from Stickler syndrome to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Monogenic hearing loss v6.7 LOXL3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LOXL3.
Monogenic hearing loss v6.7 LOXL3 Ida Ertmanska Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska edited their review of gene: LOXL3: Changed publications to: 25663169, 30362103, 34150778, 36610533, 36917121, 38957076, 41052910
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska changed review comment from: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature; to: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence:
PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
PMID: 34150778 Liu et al., 2021 - targeted deletion of Loxl3 in the inner ear caused progressive hearing loss, degeneration of hair cells and secondary degeneration of spiral ganglion neurons in mouse.
Sources: Literature
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including conductive hearing loss in 2/4 families. A mouse model with a targeted Loxl3 knockout in the inner ear caused progressive hearing loss. Hence, this gene can be promoted to Green at the next update.
Monogenic hearing loss v6.6 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram Tag Q2_26_demote_red tag was added to gene: DNMT3A.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram Classified gene: DNMT3A as Green List (high evidence)
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram Added comment: Comment on list classification: Following on the review from Terri McVeigh, request for demotion of this gene from green rating has been requested by the NHS Genomic Medicine Service and verbally agreed with PanelApp team.

This change was requested because there are no clinical guidelines to manage variants on this gene on this panel.

This change will be implemented at the next update - tagging for demotion.
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.2 DNMT3A Achchuthan Shanmugasundram Gene: dnmt3a has been classified as Green List (High Evidence).
Retinal disorders v9.3 LOXL3 Ida Ertmanska changed review comment from: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and non-specific retinal changes. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and peripheral retinal degeneration. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.3 LOXL3 Ida Ertmanska changed review comment from: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature; to: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss. On fundus examination, the father had myopic fundi and peripheral retinal degeneration - seen at age 40 years. The son, age 11 years, had vitreous degeneration/detachment in both eyes.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.1 DNMT3A Achchuthan Shanmugasundram reviewed gene: DNMT3A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v9.3 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Retinal disorders v9.3 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including retinal disease in 4 individuals from 3 unrelated families. Retinal findings included foveal hypoplasia, chorioretinal lattice degeneration, and non-specific retinal changes. A mouse model with a knock-in missense variant in LOXL3 recapitulated Stickler syndrome features, including progressive visual degeneration. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.3 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Retinal disorders v9.2 LOXL3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LOXL3.
Clefting v7.3 LOXL3 Ida Ertmanska changed review comment from: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including cleft palate in 2 unrelated families. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including clefting. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including cleft palate in 4 individuals from 2 unrelated families. Another unrelated individual presented with a high-arched palate. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including clefting. Hence, this gene should be promoted to Green at the next update.
Clefting v7.3 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Clefting v7.3 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome, including cleft palate in 2 unrelated families. A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features, including clefting. Hence, this gene should be promoted to Green at the next update.
Clefting v7.3 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Clefting v7.2 LOXL3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LOXL3.
Skeletal dysplasia v9.4 LOXL3 Ida Ertmanska reviewed gene: LOXL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25663169, 30362103, 36610533, 36917121, 38957076, 41052910; Phenotypes: Myopia 28, autosomal recessive, OMIM:619781, Stickler syndrome, MONDO:0019354; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v6.5 LOXL3 Ida Ertmanska gene: LOXL3 was added
gene: LOXL3 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Phenotypes for gene: LOXL3 were set to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Review for gene: LOXL3 was set to GREEN
Added comment: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Retinal disorders v9.2 LOXL3 Ida Ertmanska gene: LOXL3 was added
gene: LOXL3 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Phenotypes for gene: LOXL3 were set to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Review for gene: LOXL3 was set to GREEN
Added comment: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Clefting v7.2 LOXL3 Ida Ertmanska gene: LOXL3 was added
gene: LOXL3 was added to Clefting. Sources: Literature
Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOXL3 were set to 25663169; 30362103; 36610533; 36917121; 38957076; 41052910
Phenotypes for gene: LOXL3 were set to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Review for gene: LOXL3 was set to GREEN
Added comment: PMID: 41052910 Sanchez et al., 2026
3 sisters with biallelic LOXL3 variants and Stickler Syndrome. Comp het for c.1735C>T, p.Arg579* and c.956G>A, p.Arg319Gln in LOXL3 - targeted NGS panel. Parents are healthy carriers of one LOXL3 variant each. Shared phenotype: skeletal anomalies in feet and hands, cleft palate, high myopia, bilateral conductive hearing loss (2/3).

PMID: 38957076 Klejnotowska et al., 2024
4yo boy with reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed mild spondylo-epi-metaphyseal dysplasia. Normal hearing. WES revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2.

PMID: 36917121 Jiang et al., 2023
9 unrelated Chinese patients with LOXL3 variants and early-onset extreme high myopia - main and consistent feature across the cohort. No significant skeletal abnormalities, midface development, palate malformation was observed in these nine patients; auditory assessment normal where available. Authors hypothesise that biallelic missense variants result in Stickler syndrome, while truncating variants yield isolated high myopia - this is not very consistent, though.

PMID: 30362103 Chan et al., 2019
Report of a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. Clinical features: high myopia, short stature, retinal changes, high-arched palate (son only). No hearing loss.

PMID: 25663169 Alzahrani et al., 2015
Saudi family with AR Stickler syndrome. Parents are second cousins. Index patient: 16yo boy with cleft palate, micro/retrognathia, non-progressive myopia (-10.00 D) with chorioretinal lattice degeneration, mild conductive hearing loss. 8yo sister has similar presentation, with myopia of -13.00 D and normal hearing. Both had normal development. Homozygous LOXL3 c.2027G>T, p.Cys676Phe detected in the sibs (exome seq + autozygosity filtering).

Functional evidence: PMID: 36610533 Liu et al., 2023 - a mouse model of Stickler syndrome was made by inducing a LOXL3 mutation (c.2027G>A, p.Cys676Tyr) using CRISPR/Cas9. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, cleft palate, skeletal dysplasia and progressive visual degeneration.
Sources: Literature
Stickler syndrome v4.8 LOXL3 Ida Ertmanska Classified gene: LOXL3 as Amber List (moderate evidence)
Stickler syndrome v4.8 LOXL3 Ida Ertmanska Added comment: Comment on list classification: There are now 8 individuals from 4 unrelated families with biallelic LOXL3 variants and variable clinical features consistent with Stickler syndrome: high myopia (consistent finding), retinal disease (3 families), cleft palate (2 unrelated families), hearing loss (2 unrelated families), skeletal dysplasia (2 families). Another 9 patients reported in PMID: 36917121 had isolated high myopia (predominantly LOF variants). A mouse model with a knock in missense variant in LOXL3 recapitulated Stickler syndrome features. Hence, this gene should be promoted to Green at the next update.
Stickler syndrome v4.8 LOXL3 Ida Ertmanska Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Stickler syndrome v4.7 LOXL3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Stickler syndrome v4.7 LOXL3 Ida Ertmanska Phenotypes for gene: LOXL3 were changed from Stickler syndrome, MONDO:0019354 to Myopia 28, autosomal recessive, OMIM:619781; Stickler syndrome, MONDO:0019354
Stickler syndrome v4.6 LOXL3 Ida Ertmanska Publications for gene: LOXL3 were set to 25663169; 30362103
Stickler syndrome v4.5 LOXL3 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: LOXL3.
Stickler syndrome v4.5 LOXL3 Ida Ertmanska reviewed gene: LOXL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25663169, 30362103, 36610533, 36917121, 38957076, 41052910; Phenotypes: Myopia 28, autosomal recessive, OMIM:619781, Stickler syndrome, MONDO:0019354; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.10 HS6ST2 Ida Ertmanska Publications for gene: HS6ST2 were set to 30471091; 36993824; 38015989; 40686562
Intellectual disability v10.9 HS6ST2 Ida Ertmanska Publications for gene: HS6ST2 were set to 30471091; 36993824; 40686562
Albinism or congenital nystagmus v4.6 CACNB3 Achchuthan Shanmugasundram changed review comment from: PMID:41822111 (2026) reported three affected individuals from a two-generation consanguineous Lebanese family of eight members with idiopathic infantile nystagmus. All three affected individuals carried the same homozygous CACNB3 variant (c.316G>C; p.Gly106Arg), fully segregating across 8 family members. There is also functional evidence available for the p.Gly106Arg variant.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 11 May 2026), Gene2Phenotype or ClinGen.; to: PMID:41822111 (2026) reported three affected individuals from a two-generation consanguineous Lebanese family of eight members with idiopathic infantile nystagmus. All three affected individuals carried the same homozygous CACNB3 variant (c.316G>C; p.Gly106Arg), fully segregating across 8 family members. There is also functional evidence available for the p.Gly106Arg variant.

There are no other cases reported so far in the peer-reviewed literature.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 11 May 2026), Gene2Phenotype or ClinGen.
Intellectual disability v10.8 HS6ST2 Ida Ertmanska edited their review of gene: HS6ST2: Changed publications to: 30471091, 36993824, 38015989, 40686562
Intellectual disability v10.8 HS6ST2 Ida Ertmanska changed review comment from: PMID: 30471091 Paganini et al., 2019
Two Italian male twins with intellectual disability and severe myopia and an X-linked hemizygous HS6ST2 variant c.916G>C, p.Gly306Arg (maternally inherited). Psychomotor delay diagnosed at 5 years. In-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity.

PMID: 36993824 Sarmadian et al., 2023
Report of a 21mo boy from Iran, referred due to the absence of neck holding and hand tremors (manifestation of seizures). He had delayed developmental milestones such as neck holding, intellectual and walking impairment. Brain MRI showed cerebral atrophy and diffused white matter, and irregularities were seen in his EEG. He also had a ventricular septal defect. WES identified a hemizygous c.979C>T; p.Pro327Ser variant in HS6ST2 - classified as VUS, only 1 heterozygote reported in gnomAD v4.1.1.

PMID: 40686562 Zhang et al., 2025
Report of a 9 month old male Chinese proband with global developmental delay. WES detected a hemizygous c.764C>A (p.Pro255Glu) variant in HS6ST2. No abnormal vision. Brain CT scan revealed a wider left lateral ventricle compared to the contralateral ventricle.; to: PMID: 30471091 Paganini et al., 2019
Two Italian male twins with intellectual disability and severe myopia and an X-linked hemizygous HS6ST2 variant c.916G>C, p.Gly306Arg (maternally inherited). Psychomotor delay diagnosed at 5 years. In-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity.

PMID: 36993824 Sarmadian et al., 2023
Report of a 21mo boy from Iran, referred due to the absence of neck holding and hand tremors (manifestation of seizures). He had delayed developmental milestones such as neck holding, intellectual and walking impairment. Brain MRI showed cerebral atrophy and diffused white matter, and irregularities were seen in his EEG. He also had a ventricular septal defect. WES identified a hemizygous c.979C>T; p.Pro327Ser variant in HS6ST2 - classified as VUS, only 1 heterozygote reported in gnomAD v4.1.1.

PMID: 40686562 Zhang et al., 2025
Report of a 9 month old male Chinese proband with global developmental delay. WES detected a hemizygous c.764C>A (p.Pro255Glu) variant in HS6ST2. No abnormal vision. Brain CT scan revealed a wider left lateral ventricle compared to the contralateral ventricle.

Functional evidence: PMID: 38015989 Moon et al., 2024 - Knockout of Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory, providing a link to human HS6ST2-related brain disorders.
Albinism or congenital nystagmus v4.6 CACNB3 Achchuthan Shanmugasundram Classified gene: CACNB3 as Amber List (moderate evidence)
Albinism or congenital nystagmus v4.6 CACNB3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is one affected family and functional evidence available in support of the association of biallelic CACNB3 variants with infantile nystagmus. Hence, this gene should be added with amber rating on this panel.
Albinism or congenital nystagmus v4.6 CACNB3 Achchuthan Shanmugasundram Gene: cacnb3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.8 HS6ST2 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated male individuals with hemizygous HS6ST2 variants and a neurodevelopmental syndrome (ID and/or GDD) - diagnosed with so called Paganini-Miozzo syndrome. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated male individuals with hemizygous HS6ST2 variants and a neurodevelopmental syndrome (ID and/or GDD) - diagnosed with so called Paganini-Miozzo syndrome. Hence, this gene should be promoted to Green at the next update. MOI is set to X-LINKED: hemizygous mutation in males, biallelic mutations in females, as heterozygous mother of male sibs in PMID: 30471091 was not affected.
Albinism or congenital nystagmus v4.5 CACNB3 Achchuthan Shanmugasundram reviewed gene: CACNB3: Rating: AMBER; Mode of pathogenicity: None; Publications: 41822111; Phenotypes: Infantile nystagmus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.8 HS6ST2 Ida Ertmanska Publications for gene: HS6ST2 were set to
Intellectual disability v10.7 HS6ST2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Intellectual disability v10.7 HS6ST2 Ida Ertmanska Phenotypes for gene: HS6ST2 were changed from to ?Paganini-Miozzo syndrome , OMIM:301025; Paganini-Miozzo syndrome, MONDO:0026724
Intellectual disability v10.6 HS6ST2 Ida Ertmanska Mode of inheritance for gene: HS6ST2 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
Intellectual disability v10.5 HS6ST2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: HS6ST2.
Intellectual disability v10.5 HS6ST2 Ida Ertmanska Classified gene: HS6ST2 as Amber List (moderate evidence)
Intellectual disability v10.5 HS6ST2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated male individuals with hemizygous HS6ST2 variants and a neurodevelopmental syndrome (ID and/or GDD) - diagnosed with so called Paganini-Miozzo syndrome. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v10.5 HS6ST2 Ida Ertmanska Gene: hs6st2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.4 HS6ST2 Ida Ertmanska reviewed gene: HS6ST2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30471091, 36993824, 40686562; Phenotypes: ?Paganini-Miozzo syndrome , OMIM:301025; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v7.5 GNPNAT1 Ida Ertmanska Phenotypes for gene: GNPNAT1 were changed from Talipes equinovarus; Rhizomelic dysplasia, Ain-Naz type to Talipes equinovarus; ?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598; rhizomelic dysplasia, Ain-Naz type, MONDO:0859203
Fetal anomalies v7.4 GNPNAT1 Ida Ertmanska Publications for gene: GNPNAT1 were set to 39945447
Fetal anomalies v7.3 GNPNAT1 Ida Ertmanska commented on gene: GNPNAT1: Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 missense variants and skeletal dysplasia, which is detectable on fetal ultrasound. Hence, this gene should be promoted to Green at the next update.
Fetal anomalies v7.3 GNPNAT1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: GNPNAT1.
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska changed review comment from: Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 variants and skeletal dysplasia. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 missense variants and skeletal dysplasia. Hence, this gene should be promoted to Green at the next update.
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska changed review comment from: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.
In the same family, a fetus was aborted at 4 months of pregnancy due to detected skeletal deformities diagnosed intrauterine - genotype not confirmed.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Va1- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.; to: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.
In the same family, a fetus was aborted at 4 months of pregnancy due to detected skeletal deformities diagnosed intrauterine - genotype not confirmed.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Val- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska Classified gene: GNPNAT1 as Amber List (moderate evidence)
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska Added comment: Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 variants and skeletal dysplasia. Hence, this gene should be promoted to Green at the next update.
Skeletal dysplasia v9.4 GNPNAT1 Ida Ertmanska Gene: gnpnat1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v9.3 GNPNAT1 Ida Ertmanska Publications for gene: GNPNAT1 were set to 32591345
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: GNPNAT1.
Fetal anomalies v7.3 GNPNAT1 Ida Ertmanska reviewed gene: GNPNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35427807, 36097642; Phenotypes: ?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598, rhizomelic dysplasia, Ain-Naz type, MONDO:0859203; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska changed review comment from: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Va1- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.; to: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.
In the same family, a fetus was aborted at 4 months of pregnancy due to detected skeletal deformities diagnosed intrauterine - genotype not confirmed.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Va1- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska edited their review of gene: GNPNAT1: Added comment: PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Va1- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.; Changed rating: GREEN; Changed publications to: 35427807, 36097642, 39945447; Changed phenotypes to: ?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598, rhizomelic dysplasia, Ain-Naz type, MONDO:0859203; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Skeletal dysplasia v9.2 GNPNAT1 Ida Ertmanska Phenotypes for gene: GNPNAT1 were changed from Rhizomelic skeletal dysplasia to ?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598; rhizomelic dysplasia, Ain-Naz type, MONDO:0859203
Cholestasis v4.3 FOCAD Ida Ertmanska changed review comment from: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies, hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature; to: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies (85.7%), hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature
Cholestasis v4.3 FOCAD Ida Ertmanska Classified gene: FOCAD as Amber List (moderate evidence)
Cholestasis v4.3 FOCAD Ida Ertmanska Added comment: Comment on list classification: There are now numerous individuals reported with biallelic FOCAD variants and severe congenital liver disease. Liver cirrhosis in the neonatal period was a consistent finding, with several individuals needing a liver transplant before age 3 years. Hence, this gene should be promoted to Green at the next GMS update.
Cholestasis v4.3 FOCAD Ida Ertmanska Gene: focad has been classified as Amber List (Moderate Evidence).
Cholestasis v4.2 FOCAD Ida Ertmanska gene: FOCAD was added
gene: FOCAD was added to Cholestasis. Sources: Literature
Q2_26_promote_green tags were added to gene: FOCAD.
Mode of inheritance for gene: FOCAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOCAD were set to 35864190; 40662096; 41189834; 41608453
Phenotypes for gene: FOCAD were set to Liver disease, severe congenital, OMIM:619991; liver disease, severe congenital, MONDO:0859273
Review for gene: FOCAD was set to GREEN
Added comment: PMID: 35864190 Traspas et al., 2022
Report of 14 children from ten unrelated families (various ancestries, 6/10 families were consanguineous) presenting with a syndromic form of pediatric liver cirrhosis. WGS/WES detected biallelic FOCAD variants which segregate with disease. FOCAD variants detected: 3 missense, 3 stop-gain, 2 frameshift, 5 splicing, and 1 large deletion. LOF is the mechanism of disease. Absence of FOCAD protein shown in F1 and F2 individuals.

The liver phenotype was marked by cirrhosis (71.4%) with multinodularity (57.1%). Intrahepatic cholestasis was diagnosed in 35.7% of the patients, with associated jaundice (35.7%) and biliary hyperplasia (28.6%). Splenomegaly and hepatomegaly also deteced in 71% of patients. In one case, liver transplant was necessary at 6 months of age. Additional non-liver related phenotypes: abdominal distension (78.6%), diarrhea (57.1%), as well as metabolic anomalies, hernias, IUGR. Congenital cardiac and genitourinary anomalies present in 42% of patients. 6 children passed away due to hepatic or multiorgan failure (5 before age 1 year).

Moreover, focad-/- knockout zebrafish phenocopied the human disease, revealing altered mRNA degradation processes in the liver.

Further reports (articles not curated in detail):
PMID: 40662096 - Tarrell et al., 2025 - Hispanic male infant with neonatal liver disease - comp het for FOCAD c.1532A > G; p.Tyr511Cys and c.5137C > A; p.Pro1713Thr - both variants VUS, may explain milder disease progression (no liver failure or cirrhosis)
PMID: 41189834 Raja et al., 2025 - neonatal case with liver cirrhosis, required liver transplant at 3 months of age - comp het for FOCAD c.4435del p.Lys1475Asnfs* and exon 6-7 deletion
PMID: 41608453 Nuzhnaya et al., 2026 - 3yo male patient with infantile liver cirrhosis and neutropenia, homozygous for a novel FOCAD splice-site variant NM_001375570.1:c.1455 + 1G > T, p.Thr475_Val486del; liver transplant performed at 25 months

This gene is associated with AR Liver disease, severe congenital, OMIM:619991 in OMIM (Accessed 11th May 2026). Not yet curated in ClinGen or G2P.
Sources: Literature
Paediatric disorders - additional genes v8.2 FGF5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Paediatric disorders - additional genes v8.2 FGF5 Ida Ertmanska Phenotypes for gene: FGF5 were changed from Hypertrichosis; long eyelashes to Trichomegaly, OMIM:190330; trichomegaly, MONDO:0008593
Limb disorders v8.6 FAM92A Ida Ertmanska Publications for gene: FAM92A were set to 30395363
Limb disorders v8.5 FAM92A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Limb disorders v8.5 FAM92A Ida Ertmanska Phenotypes for gene: FAM92A were changed from postaxial polydactyly type A9 to ?Polydactyly, postaxial, type A9, OMIM:618219; polydactyly, postaxial, type A9, MONDO:0032603
Limb disorders v8.4 FAM92A Ida Ertmanska changed review comment from: ADDITIONAL CASE:
PMID: 38853702 Umair et al., 2024
Report of an individual homozygous for FAM92A: c.472G>C; p.Ala158Pro variant, with non-syndromic postaxial polydactyly. Seq method: WES. Consanguineous parents, both heterozygous unaffected.; to: ADDITIONAL CASE:
PMID: 38853702 Umair et al., 2024
Report of an individual homozygous for FAM92A: c.472G>C; p.Ala158Pro variant, with non-syndromic postaxial polydactyly. Seq method: WES. Variant is not reported in gnomAD v4.1.1. Consanguineous parents, both heterozygous unaffected.
Limb disorders v8.4 FAM92A Ida Ertmanska Classified gene: FAM92A as Amber List (moderate evidence)
Limb disorders v8.4 FAM92A Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated families with biallelic FAM92A (CIBAR1) variants and non-syndromic postaxial polydactyly. A mouse knockout model showed abnormal digit morphology, which supports this gene-phenotype association. Based on available evidence, this gene can be promoted to Green at the next update.
Limb disorders v8.4 FAM92A Ida Ertmanska Gene: fam92a has been classified as Amber List (Moderate Evidence).
Limb disorders v8.3 FAM92A Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: FAM92A.
Limb disorders v8.3 FAM92A Ida Ertmanska edited their review of gene: FAM92A: Added comment: ADDITIONAL CASE:
PMID: 38853702 Umair et al., 2024
Report of an individual homozygous for FAM92A: c.472G>C; p.Ala158Pro variant, with non-syndromic postaxial polydactyly. Seq method: WES. Consanguineous parents, both heterozygous unaffected.; Changed publications to: 38853702; Changed phenotypes to: ?Polydactyly, postaxial, type A9, OMIM:618219, polydactyly, postaxial, type A9, MONDO:0032603
Limb disorders v8.3 FAM92A Ida Ertmanska reviewed gene: FAM92A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v8.3 FAM92A Ida Ertmanska Tag new-gene-name tag was added to gene: FAM92A.
Intellectual disability v10.4 DPH2 Ida Ertmanska changed review comment from: ADDITIONAL CASE:
PMID: 40130534 Gowda et al., 2025
1yr 9mo old female patient with DPH2: c.1429C>T, p.Arg477* with clinical features of developmental delay, failure to thrive, sparse hair (pseudo tiger tail appearance), seizures that responded to antiepileptics, proportionate short stature, dysmorphism, and hypotonia. Neuroimaging abnormalities were cerebral atrophy, periventricular white matter hyperintensities, and prominent subarachnoid spaces. Seq method: WES.; to: ADDITIONAL CASE:
PMID: 40130534 Gowda et al., 2025
1yr 9mo old female patient with DPH2: c.1429C>T, p.Arg477* with clinical features of developmental delay, failure to thrive, sparse hair (pseudo tiger tail appearance), seizures that responded to antiepileptics, proportionate short stature, dysmorphism, and hypotonia. Neuroimaging abnormalities were cerebral atrophy, periventricular white matter hyperintensities, and prominent subarachnoid spaces. Seq method: WES.
Intellectual disability v10.4 DPH2 Ida Ertmanska Classified gene: DPH2 as Amber List (moderate evidence)
Intellectual disability v10.4 DPH2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated cases with biallelic DPH2 variants and syndromic developmental delay / intellectual disability. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v10.4 DPH2 Ida Ertmanska Gene: dph2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v10.3 DPH2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: DPH2.
Intellectual disability v10.3 DPH2 Ida Ertmanska edited their review of gene: DPH2: Added comment: ADDITIONAL CASE:
PMID: 40130534 Gowda et al., 2025
1yr 9mo old female patient with DPH2: c.1429C>T, p.Arg477* with clinical features of developmental delay, failure to thrive, sparse hair (pseudo tiger tail appearance), seizures that responded to antiepileptics, proportionate short stature, dysmorphism, and hypotonia. Neuroimaging abnormalities were cerebral atrophy, periventricular white matter hyperintensities, and prominent subarachnoid spaces. Seq method: WES.; Changed rating: GREEN; Changed publications to: 40130534; Changed phenotypes to: Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, OMIM:620062, developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MONDO:0100217; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v10.3 DPH2 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 11th May 2026.
Intellectual disability v10.3 DPH2 Ida Ertmanska Phenotypes for gene: DPH2 were changed from Diphthamide-deficiency syndrome to Developmental delay with short stature, dysmorphic facial features, and sparse hair 2, OMIM:620062; developmental delay with short stature, dysmorphic facial features, and sparse hair 2, MONDO:0100217
Monogenic hearing loss v6.4 CLIC5 Ida Ertmanska changed review comment from: ADDITIONAL CASES SINCE 2019:

PMID: 40957967 Pshennikova et al., 2026
Founder variant in Eastern Siberia: CLIC5 c.644 G>A p.(Trp215*) causes progressive AR deafness. Found in homozygous state in 22 patients from 16 unrelated families in Siberia (Russia). Hearing loss was sensorineural, symmetrical and variable by severity (from moderate to profound). Founder calculated to have arisen 78 generations ago.

PMID: 40928595 Jagannath et al., 2025
Cohort of 105 Indian individuals with hearing loss. Family 19 - proband with congenital bilateral severe-to-profound sensorineural hearing loss, homozygous for variant (CLIC5):c.401A > G, (p.Asn134Ser) - only 1 het individual in gnomAD v4.1.1. Heterozygous family members unaffected. Method: Exome seq + Sanger. *Assessed to be VUS by ACMG criteria in the article.

PMID: 33114113 Wonkam-Tingang et al., 2020
Report of a Cameroonian family with non-syndromic hearing impairment and biallelic CLIC5 variants NM_016929.5:c.224T>C; p.(L75P) and NM_016929.5: c.63+1G>A. The variants segregated with disease, with 3 affected family members carrying both variants, and other individuals being unaffected if WT or carrying one of the mutations. The 3 affected sibs were 25-36 years old, no age of onset given.; to: ADDITIONAL CASES SINCE 2019:

PMID: 40957967 Pshennikova et al., 2026
Founder variant in Eastern Siberia: CLIC5 c.644 G>A p.(Trp215*) causes progressive AR deafness. Found in homozygous state in 22 patients from 16 unrelated families in Siberia (Russia). Hearing loss was sensorineural, symmetrical and variable by severity (from moderate to profound). Founder calculated to have arisen 78 generations ago. Method: WES + Sanger.

PMID: 40928595 Jagannath et al., 2025
Cohort of 105 Indian individuals with hearing loss. Family 19 - proband with congenital bilateral severe-to-profound sensorineural hearing loss, homozygous for variant (CLIC5):c.401A > G, (p.Asn134Ser) - only 1 het individual in gnomAD v4.1.1. Heterozygous family members unaffected. Method: Exome seq + Sanger. *Assessed to be VUS by ACMG criteria in the article.

PMID: 33114113 Wonkam-Tingang et al., 2020
Report of a Cameroonian family with non-syndromic hearing impairment and biallelic CLIC5 variants NM_016929.5:c.224T>C; p.(L75P) and NM_016929.5: c.63+1G>A. The variants segregated with disease, with 3 affected family members carrying both variants, and other individuals being unaffected if WT or carrying one of the mutations. The 3 affected sibs were 25-36 years old, no age of onset given.
Monogenic hearing loss v6.4 CLIC5 Ida Ertmanska Phenotypes for gene: CLIC5 were changed from #616042:?Deafness, autosomal recessive 103; PMID: 24781754 (Nijjmegen group) progressive hearing impairment, vestibular and possibly mild renal dysfunction to Deafness, autosomal recessive 103, OMIM:616042
Monogenic hearing loss v6.3 CLIC5 Ida Ertmanska Publications for gene: CLIC5 were set to PMID:10793131; 17021174; 18028448; 24781754
Monogenic hearing loss v6.2 CLIC5 Ida Ertmanska Classified gene: CLIC5 as Amber List (moderate evidence)
Monogenic hearing loss v6.2 CLIC5 Ida Ertmanska Added comment: Comment on list classification: There are now more than 3 unrelated families reported in literature with biallelic CLIC5 variants and non-syndromic hearing loss. Hence, this gene should be promoted to Green at the next update.
Monogenic hearing loss v6.2 CLIC5 Ida Ertmanska Gene: clic5 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v6.1 CLIC5 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CLIC5.
Monogenic hearing loss v6.1 CLIC5 Ida Ertmanska reviewed gene: CLIC5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33114113, 40928595, 40957967; Phenotypes: Deafness, autosomal recessive 103, OMIM:616042; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v10.5 CLCF1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CLCF1.
Fetal anomalies v7.3 CLCF1 Ida Ertmanska Classified gene: CLCF1 as Amber List (moderate evidence)
Fetal anomalies v7.3 CLCF1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic CLCF1 variants and cold-induced sweating syndrome 2, with campodactyly and elbow contractures being a consistent feature in all 3 cases. Hence, this gene can be promoted to Green at the next update.
Fetal anomalies v7.3 CLCF1 Ida Ertmanska Gene: clcf1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v10.5 CLCF1 Ida Ertmanska Classified gene: CLCF1 as Amber List (moderate evidence)
Arthrogryposis v10.5 CLCF1 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic CLCF1 variants and cold-induced sweating syndrome 2, with campodactyly and elbow contractures being a consistent feature in all 3 cases. Hence, this gene can be promoted to Green at the next update.
Arthrogryposis v10.5 CLCF1 Ida Ertmanska Gene: clcf1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v7.2 CLCF1 Ida Ertmanska gene: CLCF1 was added
gene: CLCF1 was added to Fetal anomalies. Sources: Literature
Q2_26_promote_green tags were added to gene: CLCF1.
Mode of inheritance for gene: CLCF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLCF1 were set to 16782820; 20400119; 32512309
Phenotypes for gene: CLCF1 were set to Cold-induced sweating syndrome 2, OMIM:610313; cold-induced sweating syndrome 2, MONDO:0012467; Elbow contracture, HP:0034391; Bilateral camptodactyly, HP:0005617
Review for gene: CLCF1 was set to GREEN
Added comment: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.

This gene is associated with AR Cold-induced sweating syndrome 2, OMIM:610313 in OMIM (accessed 11th May 2026). CLCF1 is not yet associated with a condition in G2P or ClinGen.
Sources: Literature
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.

This gene is associated with AR Cold-induced sweating syndrome 2, OMIM:610313 in OMIM (accessed 11th May 2026). CLCF1 is not yet associated with a condition in G2P or ClinGen.
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling.; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling - multifocal neuronal hypoplasia phenotype.
Bleeding and platelet disorders v4.6 TUBA8 Carl Fratter reviewed gene: TUBA8: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34662886, 34704371; Phenotypes: Macrothrombocytopenia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and platelet disorders v4.6 TUBA8 Carl Fratter gene: TUBA8 was added
gene: TUBA8 was added to Bleeding and platelet disorders. Sources: NHS GMS
Mode of inheritance for gene: TUBA8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TUBA8 were set to PMID: 34662886)
Penetrance for gene: TUBA8 were set to unknown
Bleeding and platelet disorders v4.6 TUBA4A Carl Fratter gene: TUBA4A was added
gene: TUBA4A was added to Bleeding and platelet disorders. Sources: NHS GMS
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TUBA4A were set to PMID: 30760556; 36026602
Phenotypes for gene: TUBA4A were set to Macrothrombocytopenia
Penetrance for gene: TUBA4A were set to unknown
Review for gene: TUBA4A was set to AMBER
Added comment: Reviewed by regional haemostasis genomics MDT and propose amber rating.
ClinGen Gene-Disease Validity for association with AD macrothrombocytopenia has been classified as “limited”.
PMID: 30760556 – heterozygous double missense variant detected in an individual with mild macrothrombocytopenia and tubulin disorganisation in platelets; evidence for TUBA4A association with macrothrombocytopenia supported by mouse model (different variant) and other functional work demonstrating that alpha4A-tubulin is the predominant alpha-tubulin in platelets and is essential for platelet biogenesis.
PMID: 36026602 – further work in mice demonstrating importance of alpha4A-tubulin in platelets.
Vincenot et al. 2024 report 2 further families in a meeting abstract but not yet published in a peer review journal.
Sources: NHS GMS
Arthrogryposis v10.4 CLCF1 Ida Ertmanska changed review comment from: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).
; to: PMID: 32512309 Buers et al., 2020
11-year-old boy of European ancestry, homozygous for CLCF1 c.321C>G, p.Tyr107*, with Crisponi Syndrome/cold-induced sweating syndrome 2.

PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).

Functional evidence:
PMID: 19098279 Zou et al., 2009 - A complete knock-out of CLCF1 in mice is lethal at P1: underdeveloped motor neurons of the face and jaw prevent the pups from suckling.
Arthrogryposis v10.4 CLCF1 Ida Ertmanska Publications for gene: CLCF1 were set to
Arthrogryposis v10.3 CLCF1 Ida Ertmanska Phenotypes for gene: CLCF1 were changed from to Cold-induced sweating syndrome 2, OMIM:610313; cold-induced sweating syndrome 2, MONDO:0012467; Elbow contracture, HP:0034391; Bilateral camptodactyly, HP:0005617
Arthrogryposis v10.2 CLCF1 Ida Ertmanska Classified gene: CLCF1 as Amber List (moderate evidence)
Arthrogryposis v10.2 CLCF1 Ida Ertmanska Gene: clcf1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v10.1 CLCF1 Ida Ertmanska changed review comment from: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal;
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 - 24yo American woman (non-consanguineous parents, German & Irish ancestry) - excessive sweating in cold temp from age 2 years, contractures, campodactyly, unable to suck or swallow until 5 months of age, erythematous rash until age 5 years; psychomotor development was normal. Compound het for CLCF1 variants c.31_53del and c.303delC.

PMID: 16782820 Rousseau et al., 2006; to: PMID: 20400119 Hahn et al., 2010
Case 1 - female patient, Hungarian (non-consanguineous parents), 25yo - she had bilateral campodactyly (hands and feet), elbow contractures, dysmorphic features, thoracolumbar scoliosis, dry and scaly skin in neonatal period, and oral-facial weakness; from age 10 years she experienced excessive sweating triggered by cold or stressors; neurodevelopment was normal.
Case 2 - sibling of Case 1, 20yo - similarly affected, with profuse sweating in cold temperatures, difficulty sucking and swallowing in infancy, elbow contracture, campodactyly, scoliosis.
Both sibs had CLCF1 variants c.46T>C, p.Cys16Arg and c.676T>C, p.*226Argext*170 (both absent from gnomAD v4.1.1). No sequence variants detected in CRLF1
Case 3 & 4 - identical presentation, but biallelic CRLF1 variants detected.

PMID: 16782820 Rousseau et al., 2006
Australian man examined at age 46 years - he had feeding difficulties in infancy, lifelong issue of profuse sweating in cold temperatures and unable to sweat in hot conditions; also noted to have elbow contractures, campodactyly and syndactyly, thoracolumbar scoliosis and lumbar lordosis, mild sensorimotor peripheral neuropathy; brain MRI and tomography were normal. No family history. He was compound heterozygous for CLCF1 c.590G>T, p.Arg197Leu and c.321C>A, p.Tyr107* (not in gnomAD v4).
Arthrogryposis v10.1 CLCF1 Ida Ertmanska reviewed gene: CLCF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16782820, 20400119; Phenotypes: Cold-induced sweating syndrome 2, OMIM:610313, cold-induced sweating syndrome 2, MONDO:0012467; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited predisposition to acute myeloid leukaemia (AML) v3.7 CHEK2 Ida Ertmanska Tag Q2_26_expert_review tag was added to gene: CHEK2.
Inherited predisposition to acute myeloid leukaemia (AML) v3.7 CHEK2 Ida Ertmanska Classified gene: CHEK2 as Amber List (moderate evidence)
Inherited predisposition to acute myeloid leukaemia (AML) v3.7 CHEK2 Ida Ertmanska Added comment: Comment on list classification: As reviewed by Sahana Chatakondu, there are numerous individuals reported with CHEK2 variants (most often p.Ile157Thr) and myeloid malignancies. Hence, this gene will be suggested for promotion to Green on Inherited predisposition to acute myeloid leukaemia (AML), with a request of expert review to determine if the gene fits into panel scope.
Inherited predisposition to acute myeloid leukaemia (AML) v3.7 CHEK2 Ida Ertmanska Gene: chek2 has been classified as Amber List (Moderate Evidence).
Inherited predisposition to acute myeloid leukaemia (AML) v3.6 CHEK2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: CHEK2.
Tag Q2_26_NHS_review tag was added to gene: CHEK2.
Inherited predisposition to acute myeloid leukaemia (AML) v3.6 CHEK2 Ida Ertmanska changed review comment from: PMID: 40335619
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.; to: PMID: 40335619 Stubbins et al., 2025
Cohort of patients with hereditary hematopoietic malignancies. 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68–10.73, P < 0.001).
In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history.
Inherited predisposition to acute myeloid leukaemia (AML) v3.6 CHEK2 Ida Ertmanska reviewed gene: CHEK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40335619; Phenotypes: Tumor predisposition syndrome 4, breast/prostate/colorectal, OMIM:609265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pulmonary arterial hypertension v4.11 FLNA Ida Ertmanska Tag Q2_26_NHS_review tag was added to gene: FLNA.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska Tag Q2_26_NHS_review tag was added to gene: XRCC2.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska changed review comment from: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.; to: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with AR Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.
Confirmed Fanconi anaemia or Bloom syndrome v2.14 XRCC2 Ida Ertmanska changed review comment from: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247. The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.; to: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with AR Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska changed review comment from: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247. The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.; to: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247 (accessed 8th May 2026). The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska Classified gene: XRCC2 as Amber List (moderate evidence)
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with biallelic XRCC2 variants and Fanconi anaemia. All reported patients were homozygous for a recurrent p.(Arg215Ter) variant. Functional evidence is supportive of this gene-disease association. Hence, this gene should be promoted at the next GMS update.
Pigmentary skin disorders v5.2 XRCC2 Ida Ertmanska Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v5.1 XRCC2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: XRCC2.
Pigmentary skin disorders v5.1 XRCC2 Ida Ertmanska reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 42071175, 30237576; Phenotypes: ?Fanconi anemia, complementation group U, OMIM:617247; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Confirmed Fanconi anaemia or Bloom syndrome v2.14 XRCC2 Ida Ertmanska Classified gene: XRCC2 as Amber List (moderate evidence)
Confirmed Fanconi anaemia or Bloom syndrome v2.14 XRCC2 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals with biallelic XRCC2 variants and Fanconi anaemia. All reported patients were homozygous for a recurrent p.(Arg215Ter) variant. Functional evidence is supportive of this gene-disease association. Hence, this gene should be promoted at the next GMS update.
Confirmed Fanconi anaemia or Bloom syndrome v2.14 XRCC2 Ida Ertmanska Gene: xrcc2 has been classified as Amber List (Moderate Evidence).
Confirmed Fanconi anaemia or Bloom syndrome v2.13 XRCC2 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: XRCC2.
Confirmed Fanconi anaemia or Bloom syndrome v2.13 XRCC2 Ida Ertmanska changed review comment from: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247. The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.; to: PMID: 42071175 Cenciarelli et al., 2026
2 related adult individuals (19yo female and 20yo male) from a consanguineous Egyptian family, homozygous for XRCC2 p.(Arg215Ter). Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected. Diagnosed with 'Fanconi anemia-like disorder' without major hematological manifestations.

PMID: 30237576 Maddirevula et al., 2019
Report of a 3 years old Saudi girl, homozygous for XRCC2 c.643C>T:p.(Arg215*), diagnosed with XRCC2-related Fanconi anemia. At birth, she was noted to have borderline microcephaly (OFC was 33 cm); also noted to have bilateral hypoplastic thumb, multiple café late spots, strabismus, and dysmorphic facial features. She developed failure to thrive with progressive microcephaly (at age of 3 years, head circumference was 45 cm. Investigation showed pancytopenia. Chromosomal breakage was 100%. Brain MRI at 3 months of age was unremarkable.
Her parents are second cousins. Sister was similarly affected, died of respiratory failure and pancytopenia.

XRCC2 is putatively associated with Fanconi anemia, complementation group U, OMIM:617247. The gene-disease relationship was classified as Limited by ClinGen Hereditary Cancer GCEP in 2023.
Confirmed Fanconi anaemia or Bloom syndrome v2.13 XRCC2 Ida Ertmanska reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 42071175; Phenotypes: ?Fanconi anemia, complementation group U, OMIM:617247; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pulmonary arterial hypertension v4.11 FLNA Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals with monoallelic variants in FLNA and pulmonary hypertension. Hemizygous male and heterozygous females are affected (with variable penetrance and age of onset). Based on available evidence, this gene should be promoted to Green at the next update.; to: Comment on list classification: As reviewed by Karen Stals, there are more than 3 unrelated individuals with monoallelic variants in FLNA and pulmonary hypertension. Hemizygous male and heterozygous females are affected (with variable penetrance and age of onset). Based on available evidence, this gene should be promoted to Green at the next update.
Pulmonary arterial hypertension v4.11 FLNA Ida Ertmanska Publications for gene: FLNA were set to 40641615; 39510553; 30547349; 28457522
Pulmonary arterial hypertension v4.10 FLNA Ida Ertmanska edited their review of gene: FLNA: Changed publications to: 40641615, 39510553, 30557962
Pulmonary arterial hypertension v4.10 FLNA Ida Ertmanska changed review comment from: PMID: 40641615 Cai et al., 2025
29yo female (Chinese?) patient with pulmonary hypertension and a heterozygous de novo FLNA c.718 C > T, p.Q240* variant. She presented with telangiectasia, cyanosis of the lips, and hypermobility. At the age of 12, she was diagnosed with precapillary pulmonary hypertension, and patent ductus arteriosus (PDA).

PMID: 39510553 Stourm et al., 2025
Report of 9 French patients (8 female) with moderate to severe pre-capillary pulmonary hypertension, diagnosed at 0-69 years (median 36 years). Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). All patients carried LOF FLNA variants: stop-gain, frameshift, canonical splice - all P/LP according to ACMG criteria.

FLNA is associated with multiple X-linked (dominant and recessive) disease entities in OMIM. Pulmonary incompetence is a feature of several FLNA-related disorders, e.g., Cardiac valvular dysplasia, X-linked, OMIM:314400.; to: PMID: 40641615 Cai et al., 2025
29yo female (Chinese?) patient with pulmonary hypertension and a heterozygous de novo FLNA c.718 C > T, p.Q240* variant. She presented with telangiectasia, cyanosis of the lips, and hypermobility. At the age of 12, she was diagnosed with precapillary pulmonary hypertension, and patent ductus arteriosus (PDA).

PMID: 39510553 Stourm et al., 2025
Report of 9 French patients (8 female) with moderate to severe pre-capillary pulmonary hypertension, diagnosed at 0-69 years (median 36 years). Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). All patients carried LOF FLNA variants: stop-gain, frameshift, canonical splice - all P/LP according to ACMG criteria.

PMID: 30557962 Calcaterra et al., 2018
Progressive pulmonary disease in a male infant harbouring a FLNA c.7391_7403del; (p.Val2464AlafsTer5) variant. He developed significant lung disease resulting in emphysematous lesions and perivascular and interstitial fibrosis. He also exhibited general muscular hypotonia, bilateral inguinal hernia, and deformities of the lower limbs (pes tortus congenitalis and hip dysplasia). Brain MRI showed periventricular nodular heterotopia.

FLNA is associated with multiple X-linked (dominant and recessive) disease entities in OMIM. Pulmonary incompetence is a feature of several FLNA-related disorders, e.g., Cardiac valvular dysplasia, X-linked, OMIM:314400.
Pulmonary arterial hypertension v4.10 FLNA Ida Ertmanska Mode of pathogenicity for gene: FLNA was changed from None to None
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: FLNA.
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska edited their review of gene: FLNA: Changed phenotypes to: pulmonary hypertension, MONDO:0005149, Cardiac valvular dysplasia, X-linked, OMIM:314400
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska changed review comment from: PMID: 40641615 Cai et al., 2025
29yo female (Chinese?) patient with pulmonary hypertension and a heterozygous de novo FLNA c.718 C > T, p.Q240* variant. She presented with telangiectasia, cyanosis of the lips, and hypermobility. At the age of 12, she was diagnosed with precapillary pulmonary hypertension, and patent ductus arteriosus (PDA).

PMID: 39510553 Stourm et al., 2025
Report of 9 French patients (8 female) with moderate to severe pre-capillary pulmonary hypertension, diagnosed at 0-69 years (median 36 years). Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). All patients carried LOF FLNA variants: stop-gain, frameshift, canonical splice - all P/LP according to ACMG criteria.; to: PMID: 40641615 Cai et al., 2025
29yo female (Chinese?) patient with pulmonary hypertension and a heterozygous de novo FLNA c.718 C > T, p.Q240* variant. She presented with telangiectasia, cyanosis of the lips, and hypermobility. At the age of 12, she was diagnosed with precapillary pulmonary hypertension, and patent ductus arteriosus (PDA).

PMID: 39510553 Stourm et al., 2025
Report of 9 French patients (8 female) with moderate to severe pre-capillary pulmonary hypertension, diagnosed at 0-69 years (median 36 years). Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). All patients carried LOF FLNA variants: stop-gain, frameshift, canonical splice - all P/LP according to ACMG criteria.

FLNA is associated with multiple X-linked (dominant and recessive) disease entities in OMIM. Pulmonary incompetence is a feature of several FLNA-related disorders, e.g., Cardiac valvular dysplasia, X-linked, OMIM:314400.
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska Classified gene: FLNA as Amber List (moderate evidence)
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals with monoallelic variants in FLNA and pulmonary hypertension. Hemizygous male and heterozygous females are affected (with variable penetrance and age of onset). Based on available evidence, this gene should be promoted to Green at the next update.
Pulmonary arterial hypertension v4.9 FLNA Ida Ertmanska Gene: flna has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v4.8 FLNA Ida Ertmanska Phenotypes for gene: FLNA were changed from Pulmonary hypertension; respiratory failure to pulmonary hypertension, MONDO:0005149; Cardiac valvular dysplasia, X-linked, OMIM:314400
Pulmonary arterial hypertension v4.7 FLNA Ida Ertmanska Publications for gene: FLNA were set to PMID: 30547349; PMID: 28457522
Pulmonary arterial hypertension v4.6 FLNA Ida Ertmanska Mode of inheritance for gene: FLNA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pulmonary arterial hypertension v4.5 FLNA Ida Ertmanska edited their review of gene: FLNA: 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)
Pulmonary arterial hypertension v4.5 FLNA Ida Ertmanska reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: 40641615, 39510553; Phenotypes: pulmonary hypertension, MONDO:0005149; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.1 DNMT3A Terri McVeigh reviewed gene: DNMT3A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v10.2 RNU4ATAC Arina Puzriakova Publications for gene: RNU4ATAC were set to
Intellectual disability v10.1 RNU4ATAC Ida Ertmanska commented on gene: RNU4ATAC: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic RNU4ATAC variants and syndromic developmental and psychomotor delay. Hence, this gene should be promoted to Green on Intellectual disability.
Mitochondrial disorders v10.1 PTPMT1 William Macken commented on gene: PTPMT1
Limb disorders v8.3 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 reported a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 Nitoiu et al., 2025
Report of a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska commented on gene: IFT57: Comment on list classification: There are two unrelated families reported in literature with biallelic IFT57 variants: one individual reported with a diagnosis of Bardet Biedl syndrome, and one family with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. Both publications demonstrate that the IFT57 variants result in ciliary defects. However, only one individual has features consistent with Bardet Biedl syndrome. Hence, this gene can only be rated Amber on this panel, given the current evidence.
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska edited their review of gene: IFT57: Changed rating: AMBER
Limb disorders v8.3 IFT57 Ida Ertmanska Classified gene: IFT57 as Amber List (moderate evidence)
Limb disorders v8.3 IFT57 Ida Ertmanska Gene: ift57 has been classified as Amber List (Moderate Evidence).
Limb disorders v8.2 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.
Sources: Literature; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.

PMID:40273360 reported a 29-year-old male of Irish descent presenting with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome. He was identified with biallelic variants in IFT57 gene (Val397Glu/Lys225Asnfs*17).

Patient-derived fibroblasts had fewer primary cilia, abnormal ciliary morphology and abnormal anterograde transport in the primary cilia. IFT57 knockout mouse models or RPE cell lines did not form primary cilia. Rescue of IFT57 knockout primary cilia with IFT57-WT restored cilia formation while IFT57-Val397Glu only partially rescued cilia formation in Ift57-KO-mouse cells.

Sources: Literature
Limb disorders v8.2 IFT57 Ida Ertmanska gene: IFT57 was added
gene: IFT57 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: IFT57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT57 were set to 27060890; 40273360
Phenotypes for gene: IFT57 were set to ?Orofaciodigital syndrome XVIII, OMIM:617927; ciliopathy, MONDO:0005308
Review for gene: IFT57 was set to GREEN
Added comment: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.
Sources: Literature
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: IFT57.
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska Deleted their comment
Bardet Biedl syndrome v2.17 IFT57 Ida Ertmanska changed review comment from: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy no excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.; to: PMID: 27060890 Thevenon et al., 2016
3 sibs aged 17-25 years, from a consanguineous family, with oral-facial-digital syndrome with skeletal dysplasia and brachymesophalangia. No visual complaints, retinopathy not excluded in the study. All homozygous for IFT57 p.Lys259Lys. It is rare in gnomAD v4., no homozygotes reported. Variant leads to exon skipping, decrease in mRNA stability. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects’ fibroblasts compared to controls.
Renal ciliopathies v5.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Renal dysfunction was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including bilateral cystic dilations of the pronephros. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Renal dysfunction was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including bilateral cystic dilations of the pronephros. Hence, this gene should be promoted to Green at the next update.
Renal ciliopathies v5.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).
Ophthalmological ciliopathies v6.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 unrelated individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including abnormal retinal development. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are 3 unrelated individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 3 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in a ciliopathy phenotype, including abnormal retinal development. Hence, this gene should be promoted to Green at the next update.
Ophthalmological ciliopathies v6.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).
Retinal disorders v9.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 2 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in abnormal retinal development. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are 3 individuals reported in literature with biallelic BBIP1 variants and Bardet-Biedl syndrome. Retinal degeneration was confirmed in 3 unrelated patients. Moreover, zebrafish bbip1 knockdown resulted in abnormal retinal development. Hence, this gene should be promoted to Green at the next update.
Retinal disorders v9.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Functional evidence: morpholino knockdown of bbip1 in zebrafish leads to ciliopathy phenotypes: 20% of morphants present with situs inversus; morphants showed abnormal retinal development, and bilateral cystic dilations of the pronephros (an equivalent structure to the human kidney).
Bardet Biedl syndrome v2.17 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. OMIM entry states "The patient was reported to have classic features of BBS, with obesity, impaired intellectual development, polydactyly, and end-stage retinitis pigmentosa." but I was not able to verify this in the primary publication.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Limb disorders v8.1 BBIP1 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: BBIP1.
Limb disorders v8.1 BBIP1 Ida Ertmanska changed review comment from: Comment on list classification: 2 patients reported in literature with BBS and biallelic BBIP1 variants had polydactyly / brachydactyly. Hence, this gene can only be rated Amber on Limb disorders given available evidence.; to: Comment on list classification: 3 unrelated patients reported in literature with BBS and biallelic BBIP1 variants had polydactyly / brachydactyly. Hence, this gene can be updated to Green on Limb disorders at the next update.
Limb disorders v8.1 BBIP1 Ida Ertmanska changed review comment from: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD. No phenotypic details provided.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.; to: PMID: 37239474 Nawaz et al., 2023
Homozygous nonsense mutation (c.160A>T; p.Lys54Ter) in the BBIP1 (NM_001195306.1) gene in family B (Pakistani origin). Affected individual with suspected Bardet–Biedl Syndrome presented with polydactyly, retinal degeneration, obesity, hypogonadism, and renal abnormality. No ID/DD seen.

PMID: 32055034 Shamseldin et al., 2020
A patient with classical BBS (18DG0012) harboured a homozygous novel variant NM_001195305.1:c.38–6T > C (aberrant splicing confirmed by RT-PCR with 86% NMD). Phenotype: Obesity, ID, polydactyly (s/p removal), end stage RP.

PMID: 24026985 Scheidecker et al., 2014
Italian BBS patient with a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. No BBIP1 protein could be detected in fibroblasts from the patient. He presented with retinitis pigmentosa, obesity, kidney failure, cognitive disability, and brachydactyly. He was diagnosed as affected with BBS at 49 years old. He presented an end-stage renal failure 4 years after the diagnosis.
Bilateral congenital or childhood onset cataracts v8.1 PEX14 Ida Ertmanska Tag watchlist_moi tag was added to gene: PEX14.
Bilateral congenital or childhood onset cataracts v8.1 PEX14 Ida Ertmanska changed review comment from: Comment on mode of inheritance: There are 2 individuals reported with de novo heterozygous PEX14 variants and a mild peroxisome biogenesis disorder. The MOI should remain set to BIALLELIC, until more evidence emerges in support of dominant disease - added watchlist_moi tag.; to: Comment on mode of inheritance: There are 2 individuals reported with de novo heterozygous PEX14 variants and a mild peroxisome biogenesis disorder with bilateral cataracts. The MOI should remain set to BIALLELIC, until more evidence emerges in support of dominant disease - added watchlist_moi tag.
Bilateral congenital or childhood onset cataracts v8.1 PEX14 Ida Ertmanska commented on gene: PEX14: Comment on mode of inheritance: There are 2 individuals reported with de novo heterozygous PEX14 variants and a mild peroxisome biogenesis disorder. The MOI should remain set to BIALLELIC, until more evidence emerges in support of dominant disease - added watchlist_moi tag.
Bilateral congenital or childhood onset cataracts v8.1 PEX14 Ida Ertmanska reviewed gene: PEX14: Rating: GREEN; Mode of pathogenicity: None; Publications: 37493040; Phenotypes: Peroxisome biogenesis disorder 13A (Zellweger), OMIM:614887; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.1 PABPN1_GCN Ida Ertmanska Tag STR tag was added to STR: PABPN1_GCN.
Tag NGS Not Validated tag was added to STR: PABPN1_GCN.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.1 PABPN1_GCN Ida Ertmanska commented on STR: PABPN1_GCN: There is enough evidence for this STR to be green on this panel; however, this STR has not been reviewed and approved by the NHS STR working group and therefore has been rated amber. The mode of inheritance should be validated by experts, particularly to confirm whether 11 repeats are considered to be reportable in a dominant or recessive state only.
Skeletal dysplasia v9.1 GNPNAT1 Sadaf Naz reviewed gene: GNPNAT1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32591345, 35427807, 36097642; Phenotypes: Skeletal dysplasia, Rhizomelic dysplasia, Ain-Naz type; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.1 GNPNAT1 Sadaf Naz Deleted their review
Skeletal dysplasia v9.1 TMEM251 Sadaf Naz reviewed gene: TMEM251: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33252156, 40171858, 41858182; Phenotypes: Skeletal dysplasia, Dysostosis multiplex, Ain-Naz type, Mucolipidosis II-Like; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v9.1 GNPNAT1 Sadaf Naz reviewed gene: GNPNAT1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32591345, 35427807, 36097642; Phenotypes: Skeletal dysplasia, ?Rhizomelic dysplasia, Ain-Naz type; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 SEPT6 Boaz Palterer gene: SEPT6 was added
gene: SEPT6 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: SEPT6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SEPT6 were set to 42088107, 34677878
Phenotypes for gene: SEPT6 were set to Congenital neutropenia; B cell deficiency; T cell lymphopenia; Abnormal newborn screening for SCID; Hypersegmented neutrophils; Myelodysplasia; Decreased circulating B cells; Leukopenia
Penetrance for gene: SEPT6 were set to unknown
Review for gene: SEPT6 was set to GREEN
Added comment: Gunderman et al. described stop loss variant in the X-linked SEPTIN6 gene, they identified 2 hemizygous male siblings. The researchers presented evidence characterized by severe congenital neutropenia, a profound lack of circulating B cells, and variable T cell lymphopenia, noting that maternal carriers show strong negative selection against the mutated allele in their hematopoietic cells. Clinical data and bone marrow analysis revealed progressive dysmyelopoiesis with myeloid tetraploidy and a predisposition to aneuploidy, while xenograft mouse models and spatial transcriptomics further demonstrated that the SEPTIN6 mutation leads to a significant reduction in early lymphoid progenitors rather than an absolute developmental block.

Renella et al. described a single patient with a de novo germline stop-loss mutation in the X-linked gene SEPT6 with a similar phenotype
Sources: Literature
Sudden unexplained death or survivors of a cardiac event v23.2 Ida Ertmanska Panel version 23.1 has been signed off on 2026-05-06
Unexplained death in infancy and sudden unexplained death in childhood v23.2 Eleanor Williams Panel version 23.1 has been signed off on 2026-05-06
Cardiac arrhythmias v14.22 Ida Ertmanska Panel version 14.21 has been signed off on 2026-05-06
Cystic renal disease v13.3 Achchuthan Shanmugasundram Panel version 13.2 has been signed off on 2026-05-06
Rare multisystem ciliopathy Super panel v22.2 Eleanor Williams Panel version 22.1 has been signed off on 2026-05-06
Childhood onset leukodystrophy v31.3 Achchuthan Shanmugasundram Panel version 31.2 has been signed off on 2026-05-06
Other rare neuromuscular disorders v31.2 Arina Puzriakova Panel version 31.1 has been signed off on 2026-05-06
Unexplained young onset end-stage renal disease v13.2 Ida Ertmanska Panel version 13.1 has been signed off on 2026-05-06
Paediatric disorders v75.2 Eleanor Williams Panel version 75.1 has been signed off on 2026-05-06
Cerebral malformation v16.3 Achchuthan Shanmugasundram Panel version 16.2 has been signed off on 2026-05-06
Hypotonic infant v46.2 Arina Puzriakova Panel version 46.1 has been signed off on 2026-05-06
Adult-onset neurological disorders v9.4 Achchuthan Shanmugasundram Panel version 9.3 has been signed off on 2026-05-06
Hereditary ataxia and cerebellar anomalies - childhood onset v23.2 Arina Puzriakova Panel version 23.1 has been signed off on 2026-05-06
Adult-onset neurological disorders v9.2 Achchuthan Shanmugasundram Panel status changed from internal to public
Panel types changed to GMS Rare Disease Virtual; Super Panel; GMS signed-off
Renal ciliopathies v5.1 Eleanor Williams Panel version 5.0 has been signed off on 2026-05-06
Renal ciliopathies v5.0 Eleanor Williams promoted panel to version 5.0
Malformations of cortical development v8.1 Eleanor Williams Panel version 8.0 has been signed off on 2026-05-06
Malformations of cortical development v8.0 Eleanor Williams promoted panel to version 8.0
Sarcoma of possible germline origin v1.1 Achchuthan Shanmugasundram Panel version 1.0 has been signed off on 2026-05-06
Sarcoma of possible germline origin v1.0 Achchuthan Shanmugasundram promoted panel to version 1.0
Sarcoma of possible germline origin v0.9 Achchuthan Shanmugasundram Panel status changed from internal to public
Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Likely inborn error of metabolism v9.1 Ida Ertmanska Panel version 9.0 has been signed off on 2026-05-06
Embryonal tumour of possible germline origin v1.1 Achchuthan Shanmugasundram Panel version 1.0 has been signed off on 2026-05-06
Likely inborn error of metabolism v9.0 Ida Ertmanska promoted panel to version 9.0
Embryonal tumour of possible germline origin v1.0 Achchuthan Shanmugasundram promoted panel to version 1.0
Embryonal tumour of possible germline origin v0.12 Achchuthan Shanmugasundram Panel status changed from internal to public
Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Congenital myopathy v7.1 Arina Puzriakova Panel version 7.0 has been signed off on 2026-05-06
Congenital myopathy v7.0 Arina Puzriakova promoted panel to version 7.0
Dilated and arrhythmogenic cardiomyopathy v4.1 Ida Ertmanska Panel version 4.0 has been signed off on 2026-05-06
Congenital disorders of glycosylation v8.1 Arina Puzriakova Panel version 8.0 has been signed off on 2026-05-06
Childhood interstitial lung disease v1.1 Achchuthan Shanmugasundram Panel version 1.0 has been signed off on 2026-05-06
Congenital disorders of glycosylation v8.0 Arina Puzriakova promoted panel to version 8.0
Childhood interstitial lung disease v1.0 Achchuthan Shanmugasundram promoted panel to version 1.0
Adult onset dystonia, chorea or related movement disorder v6.1 Arina Puzriakova Panel version 6.0 has been signed off on 2026-05-06
Dilated and arrhythmogenic cardiomyopathy v4.0 Ida Ertmanska promoted panel to version 4.0
Adult onset dystonia, chorea or related movement disorder v6.0 Arina Puzriakova promoted panel to version 6.0
Childhood interstitial lung disease v0.11 Achchuthan Shanmugasundram Panel status changed from internal to public
Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Unexplained young onset end-stage renal disease - additional genes v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2026-05-06
Unexplained young onset end-stage renal disease - additional genes v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Monogenic short stature v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2026-05-06
Monogenic short stature v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Familial tumours of the nervous system v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2026-05-06
Familial tumours of the nervous system v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Acute intermittent porphyria v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2026-05-06
Acute intermittent porphyria v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Multi locus imprinting disorders v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2026-05-06
Multi locus imprinting disorders v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Autoinflammatory disorders v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2026-05-06
Autoinflammatory disorders v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Thrombocythaemia v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2026-05-06
Thrombocythaemia v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Osteopetrosis v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2026-05-06
Osteopetrosis v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Childhood onset dystonia, chorea or related movement disorder v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Childhood onset dystonia, chorea or related movement disorder v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Hereditary neuropathy or pain disorder v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Hereditary neuropathy or pain disorder v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Paediatric or syndromic cardiomyopathy v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Paediatric or syndromic cardiomyopathy v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Skeletal ciliopathies v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Skeletal ciliopathies v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Neurological ciliopathies v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Neurological ciliopathies v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Ophthalmological ciliopathies v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Ophthalmological ciliopathies v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Thoracic aortic aneurysm or dissection (GMS) v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Thoracic aortic aneurysm or dissection (GMS) v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Hypogonadotropic hypogonadism (GMS) v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Hypogonadotropic hypogonadism (GMS) v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Inherited phaeochromocytoma and paraganglioma excluding NF1 v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Inherited breast cancer and ovarian cancer v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2026-05-06
Inherited breast cancer and ovarian cancer v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Adult onset leukodystrophy v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Adult onset leukodystrophy v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Childhood onset hereditary spastic paraplegia v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Childhood onset hereditary spastic paraplegia v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Pigmentary skin disorders v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Pigmentary skin disorders v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Autosomal recessive primary hypertrophic osteoarthropathy v2.1 Achchuthan Shanmugasundram Panel version 2.0 has been signed off on 2026-05-06
Autosomal recessive primary hypertrophic osteoarthropathy v2.0 Achchuthan Shanmugasundram promoted panel to version 2.0
Ectodermal dysplasia v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Ectodermal dysplasia v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Respiratory ciliopathies including non-CF bronchiectasis v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Respiratory ciliopathies including non-CF bronchiectasis v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Laterality disorders and isomerism v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Laterality disorders and isomerism v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Severe insulin resistance and lipodystrophy syndromes v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Severe insulin resistance and lipodystrophy syndromes v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Cholestasis v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Cholestasis v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Possible mitochondrial disorder - nuclear genes v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Possible mitochondrial disorder - nuclear genes v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Mitochondrial disorder with complex IV deficiency v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Mitochondrial disorder with complex IV deficiency v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Mitochondrial disorder with complex I deficiency v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Mitochondrial disorder with complex I deficiency v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Cytopenia - NOT Fanconi anaemia v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Cytopenia - NOT Fanconi anaemia v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Rare anaemia v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Rare anaemia v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Thrombophilia with a likely monogenic cause v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2026-05-06
Thrombophilia with a likely monogenic cause v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Iron metabolism disorders - NOT common HFE mutations v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Iron metabolism disorders - NOT common HFE mutations v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
Structural eye disease v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Structural eye disease v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Inherited polyposis and early onset colorectal cancer - germline testing v4.1 Achchuthan Shanmugasundram Panel version 4.0 has been signed off on 2026-05-06
Inherited polyposis and early onset colorectal cancer - germline testing v4.0 Achchuthan Shanmugasundram promoted panel to version 4.0
DDG2P v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
DDG2P v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Paediatric disorders - additional genes v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Paediatric disorders - additional genes v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Fetal anomalies v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Fetal anomalies v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Ataxia and cerebellar anomalies - narrow panel v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Ataxia and cerebellar anomalies - narrow panel v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
White matter disorders and cerebral calcification - narrow panel v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
White matter disorders and cerebral calcification - narrow panel v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Adult onset neurodegenerative disorder v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Adult onset neurodegenerative disorder v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Hereditary ataxia with onset in adulthood v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Hereditary ataxia with onset in adulthood v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Early onset or syndromic epilepsy v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Early onset or syndromic epilepsy v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Primary immunodeficiency or monogenic inflammatory bowel disease v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Primary immunodeficiency or monogenic inflammatory bowel disease v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Limb disorders v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Limb disorders v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Skeletal dysplasia v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Skeletal dysplasia v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Retinal disorders v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Retinal disorders v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Neonatal diabetes v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Neonatal diabetes v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Renal tubulopathies v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Renal tubulopathies v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Intellectual disability v10.1 Achchuthan Shanmugasundram Panel version 10.0 has been signed off on 2026-05-06
Intellectual disability v10.0 Achchuthan Shanmugasundram promoted panel to version 10.0
Cystic kidney disease v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Cystic kidney disease v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Arthrogryposis v10.1 Achchuthan Shanmugasundram Panel version 10.0 has been signed off on 2026-05-06
Arthrogryposis v10.0 Achchuthan Shanmugasundram promoted panel to version 10.0
Distal myopathies v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Distal myopathies v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Congenital myaesthenic syndrome v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Congenital myaesthenic syndrome v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Bilateral congenital or childhood onset cataracts v8.1 Achchuthan Shanmugasundram Panel version 8.0 has been signed off on 2026-05-06
Bilateral congenital or childhood onset cataracts v8.0 Achchuthan Shanmugasundram promoted panel to version 8.0
Congenital muscular dystrophy v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Congenital muscular dystrophy v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Osteogenesis imperfecta v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Osteogenesis imperfecta v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Optic neuropathy v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Optic neuropathy v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Severe microcephaly v9.1 Achchuthan Shanmugasundram Panel version 9.0 has been signed off on 2026-05-06
Severe microcephaly v9.0 Achchuthan Shanmugasundram promoted panel to version 9.0
Hereditary Erythrocytosis v3.1 Achchuthan Shanmugasundram Panel version 3.0 has been signed off on 2026-05-06
Hereditary Erythrocytosis v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Nephrocalcinosis or nephrolithiasis v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Nephrocalcinosis or nephrolithiasis v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Cerebral vascular malformations v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Cerebral vascular malformations v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Congenital adrenal hypoplasia v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Congenital adrenal hypoplasia v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Inherited ovarian cancer (without breast cancer) v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Inherited ovarian cancer (without breast cancer) v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Severe early-onset obesity v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Severe early-onset obesity v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Monogenic hearing loss v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Monogenic hearing loss v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Mitochondrial disorders v10.1 Achchuthan Shanmugasundram Panel version 10.0 has been signed off on 2026-05-06
Mitochondrial disorders v10.0 Achchuthan Shanmugasundram promoted panel to version 10.0
Proteinuric renal disease v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Proteinuric renal disease v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Segmental overgrowth disorders - Deep sequencing v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Segmental overgrowth disorders - Deep sequencing v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Clefting v7.1 Achchuthan Shanmugasundram Panel version 7.0 has been signed off on 2026-05-06
Clefting v7.0 Achchuthan Shanmugasundram promoted panel to version 7.0
Holoprosencephaly v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Holoprosencephaly v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Rhabdomyolysis and metabolic muscle disorders v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Rhabdomyolysis and metabolic muscle disorders v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Primary lymphoedema v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Primary lymphoedema v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Haematological malignancies cancer susceptibility v5.1 Achchuthan Shanmugasundram Panel version 5.0 has been signed off on 2026-05-06
Haematological malignancies cancer susceptibility v5.0 Achchuthan Shanmugasundram promoted panel to version 5.0
Hypertrophic cardiomyopathy v6.1 Achchuthan Shanmugasundram Panel version 6.0 has been signed off on 2026-05-06
Hypertrophic cardiomyopathy v6.0 Achchuthan Shanmugasundram promoted panel to version 6.0
Inherited prostate cancer v1.6 Achchuthan Shanmugasundram Panel version 1.5 has been signed off on 2026-05-06
Paediatric pseudo-obstruction syndrome v2.6 Achchuthan Shanmugasundram Panel version 2.5 has been signed off on 2026-05-06
Pulmonary fibrosis familial v1.10 Achchuthan Shanmugasundram Panel version 1.9 has been signed off on 2026-05-06
Cardiac arrhythmias - additional genes v3.12 Achchuthan Shanmugasundram Panel version 3.11 has been signed off on 2026-05-06
Neurological segmental overgrowth v3.5 Achchuthan Shanmugasundram Panel version 3.4 has been signed off on 2026-05-06
Endocrine neoplasia v3.5 Achchuthan Shanmugasundram Panel version 3.4 has been signed off on 2026-05-06
Adult onset hereditary spastic paraplegia v6.11 Achchuthan Shanmugasundram Panel version 6.10 has been signed off on 2026-05-06
Multiple monogenic benign skin tumours v2.6 Achchuthan Shanmugasundram Panel version 2.5 has been signed off on 2026-05-06
Tubulointerstitial kidney disease v3.33 Achchuthan Shanmugasundram Panel version 3.32 has been signed off on 2026-05-06
Bardet Biedl syndrome v2.17 Achchuthan Shanmugasundram Panel version 2.16 has been signed off on 2026-05-06
Pyruvate dehydrogenase (PDH) deficiency v1.40 Achchuthan Shanmugasundram Panel version 1.39 has been signed off on 2026-05-06
Lysosomal storage disorder v3.6 Achchuthan Shanmugasundram Panel version 3.5 has been signed off on 2026-05-06
Glycogen storage disease v2.7 Achchuthan Shanmugasundram Panel version 2.6 has been signed off on 2026-05-06
Inherited predisposition to acute myeloid leukaemia (AML) v3.6 Achchuthan Shanmugasundram Panel version 3.5 has been signed off on 2026-05-06
Inherited pancreatic cancer v3.3 Achchuthan Shanmugasundram Panel version 3.2 has been signed off on 2026-05-06
Inherited predisposition to GIST v1.16 Achchuthan Shanmugasundram Panel version 1.15 has been signed off on 2026-05-06
Inherited renal cancer v1.29 Achchuthan Shanmugasundram Panel version 1.28 has been signed off on 2026-05-06
Common craniosynostosis syndromes v1.17 Achchuthan Shanmugasundram Panel version 1.16 has been signed off on 2026-05-06
Progressive cardiac conduction disease v2.16 Achchuthan Shanmugasundram Panel version 2.15 has been signed off on 2026-05-06
Inherited MMR deficiency (Lynch syndrome) v1.14 Achchuthan Shanmugasundram Panel version 1.13 has been signed off on 2026-05-06
Hereditary systemic amyloidosis v1.29 Achchuthan Shanmugasundram Panel version 1.28 has been signed off on 2026-05-06
Pituitary hormone deficiency v4.7 Achchuthan Shanmugasundram Panel version 4.6 has been signed off on 2026-05-06
Hypophosphataemia or rickets v4.3 Achchuthan Shanmugasundram Panel version 4.2 has been signed off on 2026-05-06
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v3.8 Achchuthan Shanmugasundram Panel version 3.7 has been signed off on 2026-05-06
Monogenic diabetes v3.22 Achchuthan Shanmugasundram Panel version 3.21 has been signed off on 2026-05-06
Congenital hyperinsulinism v3.8 Achchuthan Shanmugasundram Panel version 3.7 has been signed off on 2026-05-06
Childhood solid tumours v5.12 Achchuthan Shanmugasundram Panel version 5.11 has been signed off on 2026-05-06
Hyperthyroidism v3.6 Achchuthan Shanmugasundram Panel version 3.5 has been signed off on 2026-05-06
Short QT syndrome v3.17 Achchuthan Shanmugasundram Panel version 3.16 has been signed off on 2026-05-06
Catecholaminergic polymorphic VT v5.4 Achchuthan Shanmugasundram Panel version 5.3 has been signed off on 2026-05-06
Atypical haemolytic uraemic syndrome v3.9 Achchuthan Shanmugasundram Panel version 3.8 has been signed off on 2026-05-06
Arrhythmogenic right ventricular cardiomyopathy v3.16 Achchuthan Shanmugasundram Panel version 3.15 has been signed off on 2026-05-06
Haematuria v2.18 Achchuthan Shanmugasundram Panel version 2.17 has been signed off on 2026-05-06
Membranoproliferative glomerulonephritis including C3 glomerulopathy v3.9 Achchuthan Shanmugasundram Panel version 3.8 has been signed off on 2026-05-06
Paediatric motor neuronopathies v3.14 Achchuthan Shanmugasundram Panel version 3.13 has been signed off on 2026-05-06
Long QT syndrome v3.13 Achchuthan Shanmugasundram Panel version 3.12 has been signed off on 2026-05-06
Congenital hypothyroidism v3.4 Achchuthan Shanmugasundram Panel version 3.3 has been signed off on 2026-05-06
Brugada syndrome and cardiac sodium channel disease v3.16 Achchuthan Shanmugasundram Panel version 3.15 has been signed off on 2026-05-06
Differences in sex development v4.21 Achchuthan Shanmugasundram Panel version 4.20 has been signed off on 2026-05-06
Hereditary ataxia with onset in adulthood v8.32 Arina Puzriakova List of related panels changed from Hereditary ataxia - adult onset; R54 to Hereditary ataxia - adult onset
Panel types changed to Component Of Super Panel; GMS signed-off
Childhood solid tumours v5.11 Achchuthan Shanmugasundram List of related panels changed from Paediatric congenital malformation-dysmorphism-tumour syndrome; Paediatric congenital malformation-dysmorphism-tumour syndromes; Paediatric congenital malformation-dysmorphism-tumour sydromes; Paediatric congenital malformation-dysmorphism-tumour syndrome; Tumour predisposition - childhood onset; R359 to Paediatric congenital malformation-dysmorphism-tumour syndrome; Paediatric congenital malformation-dysmorphism-tumour syndromes; Paediatric congenital malformation-dysmorphism-tumour sydromes; Paediatric congenital malformation-dysmorphism-tumour syndrome; Tumour predisposition - childhood onset
Panel types changed to Rare Disease 100K; GMS Cancer Germline Virtual; GMS signed-off
Severe insulin resistance and lipodystrophy syndromes v4.68 Eleanor Williams Panel name changed from Lipodystrophy - childhood onset to Severe insulin resistance and lipodystrophy syndromes
List of related panels changed from R158 to Lipodystrophy - childhood onset; R158
Adult onset neurodegenerative disorder v8.22 Achchuthan Shanmugasundram List of related panels changed from Neurodegenerative disorders - adult onset; R58 to Neurodegenerative disorders - adult onset; Young onset or familial dementia; Young onset or complex Parkinson disease; Amyotrophic lateral sclerosis; Cerebral amyloid angiopathy; R58
Panel types changed to GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Paediatric disorders v72.1632 Ida Ertmanska Changed child panels to: Intellectual disability; Early onset or syndromic epilepsy; Likely inborn error of metabolism; Skeletal dysplasia; Malformations of cortical development; Paediatric disorders - additional genes; Limb disorders; White matter disorders and cerebral calcification - narrow panel; DDG2P; Clefting; Neurological ciliopathies; Skeletal ciliopathies; Monogenic hearing loss; Ophthalmological ciliopathies; Holoprosencephaly; Renal ciliopathies; Neurological segmental overgrowth
Adult onset hereditary spastic paraplegia v6.10 Achchuthan Shanmugasundram List of related panels changed from Hereditary spastic paraplegia - adult onset; R60 to Hereditary spastic paraplegia - adult onset
Panel types changed to Component Of Super Panel; GMS signed-off
Holoprosencephaly v5.12 Eleanor Williams Panel name changed from Holoprosencephaly - NOT chromosomal to Holoprosencephaly
List of related panels changed from Rhombencephalosynapsis; Holoprosencephaly; R85 to Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85
Sudden unexplained death or survivors of a cardiac event v22.60 Ida Ertmanska List of related panels changed from Molecular autopsy; Sudden cardiac death; Sudden cardiac death PILOT; R138; R425 to Molecular autopsy; Sudden cardiac death; R138
Adult onset dystonia, chorea or related movement disorder v5.6 Achchuthan Shanmugasundram List of related panels changed from Adult onset movement disorder; R56 to Adult onset movement disorder
Panel types changed to Component Of Super Panel; GMS signed-off
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 CD48 Boaz Palterer gene: CD48 was added
gene: CD48 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: CD48 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CD48 were set to 31419545
Phenotypes for gene: CD48 were set to Hemophagocytic lymphohistiocytosis; Urticaria; Hives; Inflammation; Fever; Hepatosplenomegaly
Penetrance for gene: CD48 were set to unknown
Mode of pathogenicity for gene: CD48 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: CD48 was set to RED
Added comment: Volkmer et al. described a patient with heterozygous p.S220Y causing HLH-like phenotype.
Variant is likely dominant negative
Further patient described recently validating DN mechanism:
https://rupress.org/jhi/article/2/CIS2026/eCIS2026abstract.95/281844/S220-Variants-of-Human-CD48-Result-in-Aberrant
Sources: Literature
Adult-onset neurological disorders v8.28 Achchuthan Shanmugasundram Panel status changed from public to internal
Childhood interstitial lung disease v0.10 Achchuthan Shanmugasundram Panel status changed from public to internal
Sarcoma of possible germline origin v0.8 Achchuthan Shanmugasundram Panel status changed from public to internal
Embryonal tumour of possible germline origin v0.11 Achchuthan Shanmugasundram Panel status changed from public to internal
Retinal disorders v8.129 UBAP1L Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Retinal disorders v8.129 UBAP1L Ida Ertmanska Phenotypes for gene: UBAP1L were changed from Rod-cone dystrophy, HP:0000510; cone-rod dystrophy, MONDO:0015993; retinitis pigmentosa, MONDO:0019200 to Retinal dystrophy, Zeitz-Han type, OMIM:621558; Rod-cone dystrophy, HP:0000510; cone-rod dystrophy, MONDO:0015993; retinitis pigmentosa, MONDO:0019200
Ataxia and cerebellar anomalies - narrow panel v8.87 THG1L Ida Ertmanska Phenotypes for gene: THG1L were changed from Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800, MONDO:0032923 to Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800
Haematological malignancies cancer susceptibility v4.41 NAF1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Haematological malignancies cancer susceptibility v4.41 NAF1 Ida Ertmanska Phenotypes for gene: NAF1 were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, OMIM:620365; Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma
Fetal anomalies v6.198 FAM177A1 Ida Ertmanska Phenotypes for gene: FAM177A1 were changed from Neurodevelopmental disorder with white matter abnormalities and gait disturbance to Neurodevelopmental disorder with white matter abnormalities and gait disturbance, OMIM:621152
DDG2P v6.450 FAM177A1 Ida Ertmanska Phenotypes for gene: FAM177A1 were changed from FAM177A1-related neurodevelopmental disorder with macrocephaly; MONDO:0100038 to FAM177A1-related neurodevelopmental disorder with macrocephaly; MONDO:0100038; Neurodevelopmental disorder with white matter abnormalities and gait disturbance, OMIM:621152
Intellectual disability v9.405 FAM177A1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Intellectual disability v9.405 FAM177A1 Ida Ertmanska Phenotypes for gene: FAM177A1 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder with white matter abnormalities and gait disturbance, OMIM:621152
Intellectual disability v9.404 CXorf56 Ida Ertmanska Tag gene-checked tag was added to gene: CXorf56.
Retinal disorders v8.128 C19orf44 Ida Ertmanska Tag gene-checked tag was added to gene: C19orf44.
Fetal anomalies v6.197 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Intellectual disability v9.404 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Intellectual disability v9.404 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Intellectual disability v9.403 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Structural eye disease v4.44 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Structural eye disease v4.44 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Structural eye disease v4.43 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Anophthalmia or microphthalmia v1.57 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Anophthalmia or microphthalmia v1.57 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Anophthalmia or microphthalmia v1.56 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Skeletal dysplasia v8.47 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1sy May 2026.
Skeletal dysplasia v8.47 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Skeletal dysplasia v8.46 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Cerebellar hypoplasia v1.87 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Cerebellar hypoplasia v1.87 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Cerebellar hypoplasia v1.86 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Ocular coloboma v1.52 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Ocular coloboma v1.52 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Ocular coloboma v1.51 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Limb disorders v7.35 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Limb disorders v7.35 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Limb disorders v7.34 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Chondrodysplasia punctata v1.7 C16orf62 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added on 1st May 2026.
Chondrodysplasia punctata v1.7 C16orf62 Ida Ertmanska Phenotypes for gene: C16orf62 were changed from 3C/Ritscher-Schinzel-like syndrome to Ritscher-Schinzel syndrome 3, OMIM:619135
Chondrodysplasia punctata v1.6 C16orf62 Ida Ertmanska Tag gene-checked tag was added to gene: C16orf62.
Limb disorders v7.34 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Limb disorders v7.34 TTC26 Ida Ertmanska Deleted their comment
Limb disorders v7.34 TTC26 Ida Ertmanska edited their review of gene: TTC26: Added comment: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.; Changed rating: RED
Renal ciliopathies v4.23 TTC26 Ida Ertmanska commented on gene: TTC26: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.
Renal ciliopathies v4.23 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska commented on gene: TTC26: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.
Rare multisystem ciliopathy disorders v1.182 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Rare multisystem ciliopathy disorders v1.182 TTC26 Ida Ertmanska commented on gene: TTC26
Cholestasis v3.24 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
Cholestasis v3.24 TTC26 Ida Ertmanska commented on gene: TTC26: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska commented on gene: TTC26: The 'new-gene-symbol' tag has been added as the HGNC approved official gene symbol for TTC26 is IFT56.
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska Tag new-gene-name tag was added to gene: TTC26.
DDG2P v6.449 ATXN7L3 Ida Ertmanska Phenotypes for gene: ATXN7L3 were changed from ATXN7L3-related developmental delay, hypotonia and facial dysmorphism to ATXN7L3-related developmental delay, hypotonia and facial dysmorphism; Harel-Tora neurodevelopmental syndrome, OMIM:621377
Intellectual disability v9.403 ATXN7L3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Intellectual disability v9.403 ATXN7L3 Ida Ertmanska Phenotypes for gene: ATXN7L3 were changed from syndromic neurodevelopmental disorder to Harel-Tora neurodevelopmental syndrome, OMIM:621377
Renal ciliopathies v4.23 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Neurological ciliopathies v6.21 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Fetal anomalies v6.197 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Limb disorders v7.34 TMEM17 Ida Ertmanska Tag gene-checked tag was added to gene: TMEM17.
Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 TMEFF1 Ida Ertmanska Tag gene-checked tag was added to gene: TMEFF1.
Hereditary ataxia with onset in adulthood v8.31 RAB3A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Hereditary ataxia with onset in adulthood v8.31 RAB3A Ida Ertmanska Phenotypes for gene: RAB3A were changed from RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay to Spinocerebellar ataxia 52, OMIM:621535
Hereditary ataxia with onset in adulthood v8.30 RAB3A Ida Ertmanska Tag gene-checked was removed from gene: RAB3A.
Intellectual disability v9.402 RAB3A Ida Ertmanska Phenotypes for gene: RAB3A were changed from RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay to Spinocerebellar ataxia 52, OMIM:621535
Hereditary ataxia v1.345 RAB3A Ida Ertmanska Phenotypes for gene: RAB3A were changed from RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay to Spinocerebellar ataxia 52, OMIM:621535
Ataxia and cerebellar anomalies - narrow panel v8.86 RAB3A Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Ataxia and cerebellar anomalies - narrow panel v8.86 RAB3A Ida Ertmanska Phenotypes for gene: RAB3A were changed from RAB3A associated cerebellar ataxia; pyramidal features; neurodevelopmental delay to Spinocerebellar ataxia 52, OMIM:621535
Ataxia and cerebellar anomalies - narrow panel v8.85 RAB3A Ida Ertmanska Tag gene-checked was removed from gene: RAB3A.
Retinal disorders v8.128 RNU6-1 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Retinal disorders v8.128 RNU6-1 Ida Ertmanska Phenotypes for gene: RNU6-1 were changed from retinitis pigmentosa, MONDO:0019200 to retinitis pigmentosa, MONDO:0019200; Retinitis pigmentosa 103, OMIM:621561
Retinal disorders v8.127 RNU6-1 Ida Ertmanska Tag gene-checked was removed from gene: RNU6-1.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.5 PSMC5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Rare syndromic craniosynostosis or isolated multisuture synostosis v6.5 PSMC5 Ida Ertmanska Phenotypes for gene: PSMC5 were changed from craniosynostosis, MONDO:0015469 to craniosynostosis, MONDO:0015469; Yu-Kury neurodevelopmental syndrome, OMIM:621565
Intellectual disability v9.401 PSMC5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Intellectual disability v9.401 PSMC5 Ida Ertmanska Phenotypes for gene: PSMC5 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; Yu-Kury neurodevelopmental syndrome, OMIM:621565
Intellectual disability v9.400 PSMC5 Ida Ertmanska Tag gene-checked was removed from gene: PSMC5.
DDG2P v6.448 PSMC5 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
DDG2P v6.448 PSMC5 Ida Ertmanska Phenotypes for gene: PSMC5 were changed from PSMC5-related developmental disorder (monoallelic) to PSMC5-related developmental disorder (monoallelic); Yu-Kury neurodevelopmental syndrome, OMIM:621565
DDG2P v6.447 PSMC5 Ida Ertmanska Tag gene-checked was removed from gene: PSMC5.
Monogenic short stature v1.38 GINS3 Ida Ertmanska Phenotypes for gene: GINS3 were changed from Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817 to Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817; Meier-Gorlin syndrome 9, OMIM:621512
Monogenic short stature v1.37 GINS3 Ida Ertmanska Tag gene-checked was removed from gene: GINS3.
Fetal anomalies v6.197 GINS3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype added 1st May 2026.
Fetal anomalies v6.197 GINS3 Ida Ertmanska Phenotypes for gene: GINS3 were changed from Meier-Gorlin syndrome to Meier-Gorlin syndrome; Meier-Gorlin syndrome 9, OMIM:621512
Fetal anomalies v6.196 GINS3 Ida Ertmanska Tag gene-checked was removed from gene: GINS3.
Severe microcephaly v8.53 GINS3 Ida Ertmanska Tag gene-checked was removed from gene: GINS3.
Severe microcephaly v8.53 GINS3 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 1st May 2026.
Severe microcephaly v8.53 GINS3 Ida Ertmanska Phenotypes for gene: GINS3 were changed from Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817 to Meier-Gorlin syndrome like; Meier-Gorlin syndrome, MONDO:0016817; Meier-Gorlin syndrome 9, OMIM:621512
Acute rhabdomyolysis v2.10 AMPD1 Arina Puzriakova Tag Q2_26_demote_red tag was added to gene: AMPD1.
Acute rhabdomyolysis v2.10 AMPD1 Arina Puzriakova Classified gene: AMPD1 as Green List (high evidence)
Acute rhabdomyolysis v2.10 AMPD1 Arina Puzriakova Added comment: Comment on list classification: A rating change from Green to Red was requested by NHS Genomic Medicine Service and verbally agreed with PanelApp team. This change will be implemented at the next update - tagging for demotion.
Acute rhabdomyolysis v2.10 AMPD1 Arina Puzriakova Gene: ampd1 has been classified as Green List (High Evidence).
Acute rhabdomyolysis v2.9 AMPD1 Arina Puzriakova Classified gene: AMPD1 as Green List (high evidence)
Acute rhabdomyolysis v2.9 AMPD1 Arina Puzriakova Gene: ampd1 has been classified as Green List (High Evidence).
Acute rhabdomyolysis v2.8 AMPD1 Arina Puzriakova Deleted their comment
Non-acute porphyrias v1.36 HMBS Ida Ertmanska commented on gene: HMBS: Comment on mode of inheritance: An MOI change from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal was requested by NHS Genomic Medicine Service and verbally agreed with PanelApp team. This change will be implemented at the next update - tagging for MOI change.
Non-acute porphyrias v1.36 HMBS Ida Ertmanska Tag Q2_26_MOI tag was added to gene: HMBS.
Non-acute porphyrias v1.36 HMBS Ida Ertmanska Mode of inheritance for gene: HMBS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Non-acute porphyrias v1.35 HMBS Ida Ertmanska Deleted their comment
Adult-onset neurological disorders v8.26 Achchuthan Shanmugasundram Panel status changed from internal to public
Childhood interstitial lung disease v0.9 Achchuthan Shanmugasundram Panel status changed from internal to public
Sarcoma of possible germline origin v0.7 Achchuthan Shanmugasundram Panel status changed from internal to public
Embryonal tumour of possible germline origin v0.10 Achchuthan Shanmugasundram Panel status changed from internal to public
Monogenic short stature v1.37 SHOX Achchuthan Shanmugasundram Deleted their review
Monogenic short stature v1.37 SHOX Achchuthan Shanmugasundram Classified gene: SHOX as Green List (high evidence)
Monogenic short stature v1.37 SHOX Achchuthan Shanmugasundram Gene: shox has been classified as Green List (High Evidence).
Monogenic short stature v1.36 SHOX Achchuthan Shanmugasundram Tag technical-limitations was removed from gene: SHOX.
Pigmentary skin disorders v4.21 SNAI2 Achchuthan Shanmugasundram changed review comment from: PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. One of these patients were reported with WS2 and other with WS4, and both presented with heterochromia irides and hearing loss. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss and heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.; to: PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. One of these patients were reported with WS2 and other with WS4, and both presented with heterochromia irides and hearing loss. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss or heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.
Pigmentary skin disorders v4.21 SNAI2 Achchuthan Shanmugasundram Tag watchlist tag was added to gene: SNAI2.
Pigmentary skin disorders v4.21 SNAI2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are three unrelated patients reported with monoallelic SNAI2 variants (excluding the family from Celia Moss, who has later been identified with KIT variant) and piebaldism (mild in the patient reported in PMID:24443330, who also had EDA1 variant). However, all three families reported with heterozygous variants in the recent literature (PMIDs: 30936914; 41073431) presented with Waardenburg syndrome (variants from two cases from PMID:30936914 had higher frequencies in population databases) and did not have any phenotype relevant to pigmentary skin disorders.

There are two unrelated patients reported with homozygous SNAI2 deletions and with Waardenburg syndrome. These patients presented with hearing loss and heterochromia iridis and not with any skin pigmentation phenotypes.

The MOI should therefore be updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' as the patients with biallelic variants did not present with any skin pigmentation phenotypes.

The rating should remain amber as none of the recent monoallelic cases had piebaldism and the earlier cases with piebaldism were identified with SNAI2 deletion/variants via Southern blots/ single gene sequencing. The 'watchlist' tag has been added for reviewing this gene with new evidence in the future.
Pigmentary skin disorders v4.21 SNAI2 Achchuthan Shanmugasundram Mode of inheritance for gene: SNAI2 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.400 RNU4ATAC Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: RNU4ATAC.
Intellectual disability v9.400 RNU4ATAC Ida Ertmanska reviewed gene: RNU4ATAC: Rating: GREEN; Mode of pathogenicity: None; Publications: 29391254, 36802443, 41864208; Phenotypes: RNU4ATAC spectrum disorder, MONDO:0100558; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.195 SHROOM4 Ida Ertmanska Deleted their comment
Pigmentary skin disorders v4.20 SNAI2 Achchuthan Shanmugasundram Phenotypes for gene: SNAI2 were changed from Piebaldism to Waardenburg syndrome type 2, MONDO:0019517; piebaldism, MONDO:0008244
Pigmentary skin disorders v4.19 SNAI2 Achchuthan Shanmugasundram Publications for gene: SNAI2 were set to
Early onset or syndromic epilepsy v8.195 SHROOM4 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: SHROOM4.
Early onset or syndromic epilepsy v8.195 SHROOM4 Ida Ertmanska Tag Q2_26_expert_review was removed from gene: SHROOM4.
Pigmentary skin disorders v4.18 SNAI2 Achchuthan Shanmugasundram changed review comment from: PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss and heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.; to: PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. One of these patients were reported with WS2 and other with WS4, and both presented with heterochromia irides and hearing loss. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss and heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.
Pigmentary skin disorders v4.18 SNAI2 Achchuthan Shanmugasundram reviewed gene: SNAI2: Rating: AMBER; Mode of pathogenicity: None; Publications: 12444107, 12955764, 24443330, 30936914, 41073431; Phenotypes: Waardenburg syndrome type 2, MONDO:0019517, piebaldism, MONDO:0008244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic diabetes v3.21 MAFA Achchuthan Shanmugasundram Classified gene: MAFA as Amber List (moderate evidence)
Monogenic diabetes v3.21 MAFA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Kevin Colclough, there are three unrelated families reported in published literature with heterozygous variants in MAFA gene (two families with p.Ser64Phe variant and one family with p.Thr57Arg variant) and with insulinomatosis and diabetes. There is functional evidence available from experimental studies including heterozygous MAFA p.Ser64Phe mouse model in support of the disease association.

This gene can therefore be promoted to green rating in the next GMS update.
Monogenic diabetes v3.21 MAFA Achchuthan Shanmugasundram Gene: mafa has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.20 MAFA Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with 'Insulinomatosis and diabetes mellitus' phenotype in OMIM (last accessed 29 April 2026).
Monogenic diabetes v3.20 MAFA Achchuthan Shanmugasundram Phenotypes for gene: MAFA were changed from Diabetes; Insulinomatosis; Hyperinsulinaemic Hypoglycaemia to Insulinomatosis and diabetes mellitus, OMIM:147630; islet cell adenomatosis, MONDO:0007834
Monogenic diabetes v3.19 MAFA Achchuthan Shanmugasundram Publications for gene: MAFA were set to PMID: 29339498; 34644565; 35406570; 17682063
Monogenic diabetes v3.18 MAFA Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MAFA.
Tag Q2_26_NHS_review tag was added to gene: MAFA.
Monogenic diabetes v3.18 MAFA Achchuthan Shanmugasundram reviewed gene: MAFA: Rating: GREEN; Mode of pathogenicity: None; Publications: 17682063, 29339498, 34644565, 35406570; Phenotypes: Insulinomatosis and diabetes mellitus, OMIM:147630, islet cell adenomatosis, MONDO:0007834; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Dilated and arrhythmogenic cardiomyopathy v3.13 MYLK3 Achchuthan Shanmugasundram changed review comment from: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GLHs agree that current evidence is insufficient to support haploinsufficiency of MYLK3 as a robust disease mechanism for dilated cardiomyopathy (DCM), and that loss-of-function variants in this gene should not yet be treated as clearly diagnostic. The gene shows no strong population-level constraint for heterozygous loss of function and lacks adequately powered, peer_reviewed casecontrol data and pathogenic LoF precedent needed to meet published PVS1 criteria, so variants in MYLK3 should not presently be reported as a definitive cause of disease or used to guide clinical management with high confidence.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GLHs agree that current evidence is insufficient to support haploinsufficiency of MYLK3 as a robust disease mechanism for dilated cardiomyopathy (DCM), and that loss-of-function variants in this gene should not yet be treated as clearly diagnostic. The gene shows no strong population-level constraint for heterozygous loss of function and lacks adequately powered, peer-reviewed case control data and pathogenic LoF precedent needed to meet published PVS1 criteria, so variants in MYLK3 should not presently be reported as a definitive cause of disease or used to guide clinical management with high confidence.
Fetal anomalies v6.196 ITCH Achchuthan Shanmugasundram changed review comment from: As reviewed by Ludmila Volozonoka, the single patient from PMID:36338154 is the only reported case presenting prenatally with intrauterine growth retardation. Hence, this gene can only be rated red on Fetal anomalies panel. This gene is rated with red rating on the fetal panel from PanelApp Australia.

This gene has already been rated green or proposed for green rating on panels relevant for this multi-system phenotype such as R15 Primary immunodeficiency or monogenic inflammatory bowel disease, R413 Autoinflammatory disorders and R27 Paediatric disorders (via DDG2P panel).; to: As reviewed by Ludmila Volozonoka, the single patient from PMID:36338154 is the only reported case presenting prenatally with intrauterine growth retardation. Hence, this gene can only be rated red on Fetal anomalies panel. This gene is rated with red rating on the fetal panel from PanelApp Australia.

This gene has been associated with 'Autoimmune disease, multisystem, with facial dysmorphism' phenotype (MIM #613385) in OMIM (last accessed 29 April 2026).

This gene has already been rated green or proposed for green rating on panels relevant for this multi-system phenotype such as R15 Primary immunodeficiency or monogenic inflammatory bowel disease, R413 Autoinflammatory disorders and R27 Paediatric disorders (via DDG2P panel).
Fetal anomalies v6.196 ITCH Achchuthan Shanmugasundram Phenotypes for gene: ITCH were changed from Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 to Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385; syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245
Fetal anomalies v6.195 ITCH Achchuthan Shanmugasundram Publications for gene: ITCH were set to 20170897; 31091003
Fetal anomalies v6.194 ITCH Achchuthan Shanmugasundram edited their review of gene: ITCH: Added comment: As reviewed by Ludmila Volozonoka, the single patient from PMID:36338154 is the only reported case presenting prenatally with intrauterine growth retardation. Hence, this gene can only be rated red on Fetal anomalies panel. This gene is rated with red rating on the fetal panel from PanelApp Australia.

This gene has already been rated green or proposed for green rating on panels relevant for this multi-system phenotype such as R15 Primary immunodeficiency or monogenic inflammatory bowel disease, R413 Autoinflammatory disorders and R27 Paediatric disorders (via DDG2P panel).; Changed rating: RED; Changed publications to: 36338154; Changed phenotypes to: Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385, syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram changed review comment from: PMID:28005958 (2016) reported a cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES, of which one patient reported with non-syndromic inherited retinal dystrophy was identified with compound heterozygous variants in SCLT1 gene.

PMID:37734845 (2023) reported a cohort of 1,000 probands with inherited retinal degeneration or inherited optic neuropathy, of which one patient with cone-rod dystrophy was identified to carry a heterozygous canonical splice site variant (predicted to alter the splice acceptor site of intron 15) in trans with a 1.4 kb deletion of the last coding exon (exon 21).

PMID:41963357 (2026) reported seven patients from six unrelated families with clinical phenotypes of retinal degeneration (early-onset severe retinal dystrophy or rod-cone dystrophy) associated with rare biallelic variants in SCLT1 gene. Five of these families were clearly or presumed to be diagnosed with autosomal recessive non-syndromic IRD and one with mild syndromic IRD. Ten different variants were identified in these patients, of which eight are novel variants. Five of ten variants affected splicing and one of the detected variants was a ~76kb in-frame tandem duplication encompassing exon 3-10 of the gene.; to: SCLT1 gene has previously been associated with autosomal recessive syndromic ciliopathies and rated green on relevant panels.

PMID:28005958 (2016) reported a cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES, of which one patient reported with non-syndromic inherited retinal dystrophy was identified with compound heterozygous variants in SCLT1 gene.

PMID:37734845 (2023) reported a cohort of 1,000 probands with inherited retinal degeneration or inherited optic neuropathy, of which one patient with cone-rod dystrophy was identified to carry a heterozygous canonical splice site variant (predicted to alter the splice acceptor site of intron 15) in trans with a 1.4 kb deletion of the last coding exon (exon 21).

PMID:41963357 (2026) reported seven patients from six unrelated families with clinical phenotypes of retinal degeneration (early-onset severe retinal dystrophy or rod-cone dystrophy) associated with rare biallelic variants in SCLT1 gene. Five of these families were clearly or presumed to be diagnosed with autosomal recessive non-syndromic IRD and one with mild syndromic IRD. Ten different variants were identified in these patients, of which eight are novel variants. Five of ten variants affected splicing and one of the detected variants was a ~76kb in-frame tandem duplication encompassing exon 3-10 of the gene.
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Tracy Lester, there is sufficient evidence available (>5 unrelated families) for the association of biallelic SCLT1 variants with non-syndromic inherited retinal dystrophy. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Tracy Lester, there is sufficient evidence available (>5 unrelated families) for the association of biallelic SCLT1 variants with non-syndromic inherited retinal dystrophy. Hence, this gene can be promoted to green rating in the next GMS update.
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram Classified gene: SCLT1 as Amber List (moderate evidence)
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Tracy Lester, there is sufficient evidence available (>5 unrelated families) for the association of biallelic SCLT1 variants with non-syndromic inherited retinal dystrophy. Hence, this gene can be promoted to green rating in the next GMS update.
Retinal disorders v8.127 SCLT1 Achchuthan Shanmugasundram Gene: sclt1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v8.126 SCLT1 Achchuthan Shanmugasundram Phenotypes for gene: SCLT1 were changed from retinal dystrophy to Retinal dystrophy, HP:0000556
Retinal disorders v8.125 SCLT1 Achchuthan Shanmugasundram Publications for gene: SCLT1 were set to 41963357; 37734845
Retinal disorders v8.124 SCLT1 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: SCLT1.
Tag Q2_26_NHS_review tag was added to gene: SCLT1.
Retinal disorders v8.124 SCLT1 Achchuthan Shanmugasundram reviewed gene: SCLT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28005958, 37734845, 41963357; Phenotypes: Retinal dystrophy, HP:0000556; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v4.5 CACNB3 Mervyn Thomas gene: CACNB3 was added
gene: CACNB3 was added to Albinism or congenital nystagmus. Sources: Literature
Mode of inheritance for gene: CACNB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNB3 were set to 41822111
Phenotypes for gene: CACNB3 were set to infantile nystagmus
Penetrance for gene: CACNB3 were set to Complete
Review for gene: CACNB3 was set to GREEN
Added comment: Recent evidence suggests this gene can be involved in infantile nystagmus please see publication - https://pubmed.ncbi.nlm.nih.gov/41822111/
Sources: Literature
Pulmonary arterial hypertension v4.5 FLNA Karen Stals gene: FLNA was added
gene: FLNA was added to Pulmonary arterial hypertension. Sources: Literature
Mode of inheritance for gene: FLNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FLNA were set to PMID: 30547349; PMID: 28457522
Phenotypes for gene: FLNA were set to Pulmonary hypertension; respiratory failure
Review for gene: FLNA was set to GREEN
gene: FLNA was marked as current diagnostic
Added comment: Multiple papers report loss of function FLNA variants as a cause of neonatal/childhood pulmonary hypertension (see PMID: 30547349), GeneReviews FLNA deficiency page lists pulmonary findings including pulmonary hypertension in list of clinical features.
Sources: Literature
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. 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.; to: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. 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.
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. 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.
Intellectual disability v9.400 PGBD5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Severe developmental delay/ intellectual disability was reported in all ten patients. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Severe developmental delay/ intellectual disability was reported in all ten patients. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.85 PGBD5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Ataxia was reported in seven patients from four of these five families. Cerebellar atrophy was also reported in some patients. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Ataxia was reported in seven patients from four of these five families. Cerebellar atrophy was also reported in some patients. 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.
Childhood onset hereditary spastic paraplegia v8.53 PGBD5 Achchuthan Shanmugasundram Classified gene: PGBD5 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.53 PGBD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are ten patients from five unrelated families reported with biallelic PGBD5 variants and neurodevelopmental disorder. Spasticity was reported in five patients from three families. 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.
Childhood onset hereditary spastic paraplegia v8.53 PGBD5 Achchuthan Shanmugasundram Gene: pgbd5 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.85 PGBD5 Achchuthan Shanmugasundram Classified gene: PGBD5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.85 PGBD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Ataxia was reported in seven patients from four of these five families. Cerebellar atrophy was also reported in some patients. Hence, this gene can be promoted to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v8.85 PGBD5 Achchuthan Shanmugasundram Gene: pgbd5 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.52 PGBD5 Achchuthan Shanmugasundram gene: PGBD5 was added
gene: PGBD5 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q2_26_promote_green tags were added to gene: PGBD5.
Mode of inheritance for gene: PGBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGBD5 were set to 41533792
Phenotypes for gene: PGBD5 were set to Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Review for gene: PGBD5 was set to GREEN
Added comment: PMID:41533792 (2026) reported the identification of genetic variants in PGBD5 gene using GeneMatcher in ten individuals from five unrelated consanguineous families. Exome sequencing was used to identify distinct homozygous PGBD5 variants segregating with the affected family members and this was confirmed by Sanger sequencing. These affected children shared conserved clinical phenotypes across neurodevelopmental and motor domains.

Neurodevelopmental features included intellectual disability and developmental delay (ID/DD; ten of ten), epilepsy (nine of nine), limited or no speech (nine of nine), autism spectrum disorder, or social delay (ASD; four of six). Prominent motor features included axial hypotonia (nine of nine), increased peripheral tone (seven of nine) or decreased peripheral tone (two of nine), increased tendon reflexes (five of nine), or decreased tendon reflexes (four of nine). Other observed neurological phenotypes include spasticity that mainly affected the lower limbs (five of nine), intermittent dystonia (three of ten), and ataxia (seven of ten).

There is also evidence available from Pgbd5-null mice, which were runted and had significantly smaller brains compared to wildtype. Mutant mice showed increased locomotor activity, reduced anxiety-like behavior, impaired motor coordination, increased susceptibility to seizures, and decreased cortical volume on brain MRI. Analysis of neurons derived from Pgbd5-null mouse brains showed reduced DNA breakage and repair in postmitotic neuronal precursors during cortical development compared to controls.

This gene has already been associated with relevant phenotype in OMIM (MIM #41533792, last accessed 28 April 2026), but not yet in Gene2Phenotype.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.84 PGBD5 Achchuthan Shanmugasundram gene: PGBD5 was added
gene: PGBD5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q2_26_promote_green tags were added to gene: PGBD5.
Mode of inheritance for gene: PGBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGBD5 were set to 41533792
Phenotypes for gene: PGBD5 were set to Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Review for gene: PGBD5 was set to GREEN
Added comment: PMID:41533792 (2026) reported the identification of genetic variants in PGBD5 gene using GeneMatcher in ten individuals from five unrelated consanguineous families. Exome sequencing was used to identify distinct homozygous PGBD5 variants segregating with the affected family members and this was confirmed by Sanger sequencing. These affected children shared conserved clinical phenotypes across neurodevelopmental and motor domains.

Neurodevelopmental features included intellectual disability and developmental delay (ID/DD; ten of ten), epilepsy (nine of nine), limited or no speech (nine of nine), autism spectrum disorder, or social delay (ASD; four of six). Prominent motor features included axial hypotonia (nine of nine), increased peripheral tone (seven of nine) or decreased peripheral tone (two of nine), increased tendon reflexes (five of nine), or decreased tendon reflexes (four of nine). Other observed neurological phenotypes include spasticity that mainly affected the lower limbs (five of nine), intermittent dystonia (three of ten), and ataxia (seven of ten).

There is also evidence available from Pgbd5-null mice, which were runted and had significantly smaller brains compared to wildtype. Mutant mice showed increased locomotor activity, reduced anxiety-like behavior, impaired motor coordination, increased susceptibility to seizures, and decreased cortical volume on brain MRI. Analysis of neurons derived from Pgbd5-null mouse brains showed reduced DNA breakage and repair in postmitotic neuronal precursors during cortical development compared to controls.

This gene has already been associated with relevant phenotype in OMIM (MIM #41533792, last accessed 28 April 2026), but not yet in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram Classified gene: PGBD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Epilepsy was reported in nine of these ten patients. Hence, this gene can be promoted to green rating in the next GMS update.
Early onset or syndromic epilepsy v8.195 PGBD5 Achchuthan Shanmugasundram Gene: pgbd5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.194 PGBD5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: PGBD5.
Tag Q2_26_NHS_review tag was added to gene: PGBD5.
Early onset or syndromic epilepsy v8.194 PGBD5 Achchuthan Shanmugasundram Phenotypes for gene: PGBD5 were changed from Seizures; global developmental delay; spasticity; hypotonia to Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Early onset or syndromic epilepsy v8.193 PGBD5 Achchuthan Shanmugasundram Publications for gene: PGBD5 were set to PMID: 41533792
Early onset or syndromic epilepsy v8.192 PGBD5 Achchuthan Shanmugasundram reviewed gene: PGBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 41533792; Phenotypes: Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482, neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.400 PGBD5 Achchuthan Shanmugasundram Classified gene: PGBD5 as Amber List (moderate evidence)
Intellectual disability v9.400 PGBD5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Karen Stals, there are ten patients from five unrelated families reported with biallelic PGBD5 variants and a neurodevelopmental disorder. Severe developmental delay/ intellectual disability was reported in all ten patients. Hence, this gene can be promoted to green rating in the next GMS update.
Intellectual disability v9.400 PGBD5 Achchuthan Shanmugasundram Gene: pgbd5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.399 PGBD5 Achchuthan Shanmugasundram Phenotypes for gene: PGBD5 were changed from Seizures; global developmental delay; spasticity; hypotonia to Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Intellectual disability v9.398 PGBD5 Achchuthan Shanmugasundram edited their review of gene: PGBD5: Changed phenotypes to: Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482, neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO:0980968
Intellectual disability v9.398 PGBD5 Achchuthan Shanmugasundram Publications for gene: PGBD5 were set to PMID: 41533792
Intellectual disability v9.397 PGBD5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: PGBD5.
Tag Q2_26_NHS_review tag was added to gene: PGBD5.
Intellectual disability v9.397 PGBD5 Achchuthan Shanmugasundram commented on gene: PGBD5: PMID:41533792 (2026) reported the identification of genetic variants in PGBD5 gene using GeneMatcher in ten individuals from five unrelated consanguineous families. Exome sequencing was used to identify distinct homozygous PGBD5 variants segregating with the affected family members and this was confirmed by Sanger sequencing. These affected children shared conserved clinical phenotypes across neurodevelopmental and motor domains.

Neurodevelopmental features included intellectual disability and developmental delay (ID/DD; ten of ten), epilepsy (nine of nine), limited or no speech (nine of nine), autism spectrum disorder, or social delay (ASD; four of six). Prominent motor features included axial hypotonia (nine of nine), increased peripheral tone (seven of nine) or decreased peripheral tone (two of nine), increased tendon reflexes (five of nine), or decreased tendon reflexes (four of nine). Other observed neurological phenotypes include spasticity that mainly affected the lower limbs (five of nine), intermittent dystonia (three of ten), and ataxia (seven of ten).

There is also evidence available from Pgbd5-null mice, which were runted and had significantly smaller brains compared to wildtype. Mutant mice showed increased locomotor activity, reduced anxiety-like behavior, impaired motor coordination, increased susceptibility to seizures, and decreased cortical volume on brain MRI. Analysis of neurons derived from Pgbd5-null mouse brains showed reduced DNA breakage and repair in postmitotic neuronal precursors during cortical development compared to controls.

This gene has already been associated with relevant phenotype in OMIM (MIM #41533792, last accessed 28 April 2026), but not yet in Gene2Phenotype.
Intellectual disability v9.397 PGBD5 Achchuthan Shanmugasundram reviewed gene: PGBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 41533792; Phenotypes: Neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, OMIM:621482, neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, MONDO_0980968; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.45 SMN1 Eleanor Williams Tag Q2_26_expert_review tag was added to gene: SMN1.
Paediatric motor neuronopathies v3.13 SMN1 Eleanor Williams Tag Q2_26_expert_review tag was added to gene: SMN1.
Arthrogryposis v9.34 SMN1 Eleanor Williams Tag Q2_26_expert_review tag was added to gene: SMN1.
Fetal anomalies v6.194 SMN1 Eleanor Williams commented on gene: SMN1: Added the Q2_26_demote_red and currently-ngs-nonreportable tags due to limitations in reporting SNVs in this gene. It needs to be confirmed whether variants in this gene can be reported in this test by the labs.
Fetal anomalies v6.194 SMN1 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: SMN1.
Tag Q2_26_demote_red tag was added to gene: SMN1.
Tag Q2_26_expert_review tag was added to gene: SMN1.
Hereditary neuropathy or pain disorder v7.45 SMN1 Eleanor Williams commented on gene: SMN1: Added the Q2_26_demote_red and currently-ngs-nonreportable tags due to limitations in reporting SNVs in this gene.
Hereditary neuropathy or pain disorder v7.45 SMN1 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: SMN1.
Tag Q2_26_demote_red tag was added to gene: SMN1.
Paediatric motor neuronopathies v3.13 SMN1 Eleanor Williams commented on gene: SMN1: Added the Q2_26_demote_red and currently-ngs-nonreportable tags due to limitations in reporting SNVs in this gene.
Paediatric motor neuronopathies v3.13 SMN1 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: SMN1.
Tag Q2_26_demote_red tag was added to gene: SMN1.
Arthrogryposis v9.34 SMN1 Eleanor Williams commented on gene: SMN1: Added the Q2_26_demote_red and currently-ngs-nonreportable tags due to limitations in reporting SNVs in this gene.
Arthrogryposis v9.34 SMN1 Eleanor Williams Tag Q2_26_demote_red tag was added to gene: SMN1.
Arthrogryposis v9.34 SMN1 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: SMN1.
Parkinson Disease and Complex Parkinsonism v1.128 GBA Anjali Lloyd-Jani reviewed gene: GBA: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29385658; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v5.73 HGF Ida Ertmanska Tag watchlist was removed from gene: HGF.
Fetal anomalies v6.194 SKOR2 Eleanor Williams Phenotypes for gene: SKOR2 were changed from Cerebellar hypoplasia, neurodevelopmental delay to Cerebellar hypoplasia, neurodevelopmental delay; Valence-Farazi cerebellar ataxia syndrome, OMIM: 621386; Valence-Farazi cerebellar ataxia syndrome, MONDO:0980707
Limb disorders v7.34 TTC26 Eleanor Williams Tag Q2_26_promote_green was removed from gene: TTC26.
Tag curated_removed tag was added to gene: TTC26.
Limb disorders v7.34 TTC26 Eleanor Williams Classified gene: TTC26 as No list
Limb disorders v7.34 TTC26 Eleanor Williams Added comment: Comment on list classification: In line with other multisystem ciliopathy genes, this gene has been removed from the limb disorders panel and will be tested through the Rare multisystem ciliopathy Super panel https://panelapp.genomicsengland.co.uk/panels/728/
Limb disorders v7.34 TTC26 Eleanor Williams Gene: ttc26 has been removed from the panel.
Fetal anomalies v6.193 SNAPIN Eleanor Williams Phenotypes for gene: SNAPIN were changed from neurodevelopmental disorder; Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393 to neurodevelopmental disorder; Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Severe microcephaly v8.52 SNAPIN Eleanor Williams Phenotypes for gene: SNAPIN were changed from Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393 to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Ataxia and cerebellar anomalies - narrow panel v8.83 SNAPIN Eleanor Williams Phenotypes for gene: SNAPIN were changed from Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393 to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Retinal disorders v8.124 SCLT1 Tracy Lester gene: SCLT1 was added
gene: SCLT1 was added to Retinal disorders. Sources: NHS GMS
Mode of inheritance for gene: SCLT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCLT1 were set to 41963357; 37734845
Phenotypes for gene: SCLT1 were set to retinal dystrophy
Penetrance for gene: SCLT1 were set to unknown
Review for gene: SCLT1 was set to GREEN
Added comment: The authors describe five families with non-syndromic IRD and compound heterozygous for SLCT1 variants - 8 variants were novel. 4 missense, 2 single AA dels, 3 intronic. Four of these variants shown to impact splicing. A large in-frame tandem dup also reported. Another comp het case with IRD reported by Weisschuh et al
Meets criteria to be green on R32 panel.
Sources: NHS GMS
Adult onset neurodegenerative disorder v8.21 FIG4 Anjali Lloyd-Jani reviewed gene: FIG4: 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: PMID: 19118816; Phenotypes: Autosomal recessive Yunis-Varon syndrome and CMT4J; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v4.5 MLPH Achchuthan Shanmugasundram Classified gene: MLPH as Amber List (moderate evidence)
Albinism or congenital nystagmus v4.5 MLPH Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (over 10 unrelated cases and functional evidence) for the association of this gene with Griscelli syndrome, type 3 (MIM #609227). Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Albinism or congenital nystagmus v4.5 MLPH Achchuthan Shanmugasundram Gene: mlph has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v4.4 MLPH Achchuthan Shanmugasundram Phenotypes for gene: MLPH were changed from Griscelli syndrome, type 3 609227 AR to Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, MONDO:0012220
Albinism or congenital nystagmus v4.3 MLPH Achchuthan Shanmugasundram Publications for gene: MLPH were set to
Albinism or congenital nystagmus v4.2 MLPH Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MLPH.
Albinism or congenital nystagmus v4.2 MLPH Achchuthan Shanmugasundram reviewed gene: MLPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 12897212, 21883982, 22711375, 26337734, 30389201, 31721180, 35602484; Phenotypes: Griscelli syndrome, type 3, OMIM:609227, Griscelli syndrome type 3, MONDO:0012220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v4.18 MLPH Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Veronica Kinsler, there is sufficient evidence available (over 10 unrelated cases and functional evidence) for the association of this gene with Griscelli syndrome, type 3 (MIM #609227). Hence, this gene can be promoted to green rating on this panel.; to: Comment on list classification: As reviewed by Veronica Kinsler, there is sufficient evidence available (over 10 unrelated cases and functional evidence) for the association of this gene with Griscelli syndrome, type 3 (MIM #609227). Hence, this gene can be promoted to green rating on this panel in the next GMS update.
Pigmentary skin disorders v4.18 MLPH Achchuthan Shanmugasundram Classified gene: MLPH as Amber List (moderate evidence)
Pigmentary skin disorders v4.18 MLPH Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Veronica Kinsler, there is sufficient evidence available (over 10 unrelated cases and functional evidence) for the association of this gene with Griscelli syndrome, type 3 (MIM #609227). Hence, this gene can be promoted to green rating on this panel.
Pigmentary skin disorders v4.18 MLPH Achchuthan Shanmugasundram Gene: mlph has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v4.17 MLPH Achchuthan Shanmugasundram edited their review of gene: MLPH: Changed phenotypes to: Griscelli syndrome, type 3, OMIM:609227, Griscelli syndrome type 3, MONDO:0012220
Pigmentary skin disorders v4.17 MLPH Achchuthan Shanmugasundram Phenotypes for gene: MLPH were changed from Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, Griscelli syndrome type 3, MONDO:0012220 to Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, MONDO:0012220
Pigmentary skin disorders v4.16 MLPH Achchuthan Shanmugasundram Phenotypes for gene: MLPH were changed from Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, Griscelli syndrome type 3 to Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, Griscelli syndrome type 3, MONDO:0012220
Pigmentary skin disorders v4.15 MLPH Achchuthan Shanmugasundram edited their review of gene: MLPH: Changed phenotypes to: Griscelli syndrome, type 3, OMIM:609227, Griscelli syndrome type 3, Griscelli syndrome type 3, MONDO:0012220
Pigmentary skin disorders v4.15 MLPH Achchuthan Shanmugasundram Phenotypes for gene: MLPH were changed from to Griscelli syndrome, type 3, OMIM:609227; Griscelli syndrome type 3, Griscelli syndrome type 3
Pigmentary skin disorders v4.14 MLPH Achchuthan Shanmugasundram Publications for gene: MLPH were set to
Pigmentary skin disorders v4.13 MLPH Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: MLPH.
Tag Q2_26_NHS_review tag was added to gene: MLPH.
Pigmentary skin disorders v4.13 MLPH Achchuthan Shanmugasundram reviewed gene: MLPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 12897212, 21883982, 22711375, 26337734, 30389201, 31721180, 35602484; Phenotypes: Griscelli syndrome, type 3, OMIM:609227, Griscelli syndrome type 3, Griscelli syndrome type 3; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v7.25 ATAD1 Achchuthan Shanmugasundram Classified gene: ATAD1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v7.25 ATAD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of biallelic variants with hyperekplexia. As other hyperekplexia-causing genes (e.g. GLRA1 & GLRB) are rated green on this panel, this gene should also be rated green in the next update.
Childhood onset dystonia, chorea or related movement disorder v7.25 ATAD1 Achchuthan Shanmugasundram Gene: atad1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.24 ATAD1 Achchuthan Shanmugasundram gene: ATAD1 was added
gene: ATAD1 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Q2_26_promote_green tags were added to gene: ATAD1.
Mode of inheritance for gene: ATAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD1 were set to 28180185; 29390050; 29659736; 33134516; 36933275
Phenotypes for gene: ATAD1 were set to Hyperekplexia 4, OMIM:618011; hyperekplexia 4, MONDO:0044330
Review for gene: ATAD1 was set to GREEN
Added comment: PMID:28180185 (2017) reported the identification of a homozygous nonsense variant in ATAD1 gene (p.Glu276Ter) in a large consanguineous Kuwaiti family. They presented with a neurological disorder characterised by hypertonia, seizures, and death. Detailed clinical information was available for two of the patients and they had no or little spontaneous movement. There is also functional evidence available from ATAD1 knockout mouse model, from which the authors suggested loss-of-function mechanism for the variant.

PMID:29390050 (2018) reported the identification of a homozygous frameshift variant in ATAD1 gene (p.His357Argfs*15) in three siblings from a consanguineous Tunisian family who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. The proband had exaggerated startle and clonic movements. Functional evidence was available which suggested that gain-of-function for the variant.

PMID:29659736 (2018) reported a female infant born of consanguineous parents with a similar disorder. She was identified with a homozygous ATAD1 variant (c.162G-C) that was predicted to result in a missense variant or a splicing defect causing loss of function. She was a stiff baby at birth and had no spontaneous movements.

PMID:33134516 (2020) reported two new unrelated patients presenting with a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. They were identified with homozygous variants in ATAD1 gene (Patient 1: p.His357Argfs*15; Patient 2: p.Gly128Val).

PMID:36933275 (2023) reported the identification of two novel heterozygous variants in ATAD1 gene (maternal: c.690+1G>c - splice site variant; paternal: c.148G>T - nonsense) in a female neonate presenting with hypertonia, tremulousness and clonus.

This gene has been associated with hyperekplexia 4 in OMIM (MIM #618011, last accessed 23 April 2026), but not in Gene2Phenotype or ClinGen.
Sources: Literature
Likely inborn error of metabolism v8.113 SLC6A5 Achchuthan Shanmugasundram Classified gene: SLC6A5 as Amber List (moderate evidence)
Likely inborn error of metabolism v8.113 SLC6A5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants with hyperekplexia 3. This gene encodes a metabolite transporter and is rated definitive by General Inborn Errors of Metabolism GCEP for biallelic variants. This gene should therefore be promoted to green rating on R98 in the next GMS update.
Likely inborn error of metabolism v8.113 SLC6A5 Achchuthan Shanmugasundram Gene: slc6a5 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v8.112 SLC6A5 Achchuthan Shanmugasundram gene: SLC6A5 was added
gene: SLC6A5 was added to Likely inborn error of metabolism. Sources: Literature
Q2_26_promote_green tags were added to gene: SLC6A5.
Mode of inheritance for gene: SLC6A5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SLC6A5 were set to 16751771; 22753417
Phenotypes for gene: SLC6A5 were set to Hyperekplexia 3, OMIM:614618; hyperekplexia 3, MONDO:0013827
Review for gene: SLC6A5 was set to GREEN
Added comment: PMID:16751771 (2006) reported seven patients from six unrelated families presenting with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnoea episodes. Of these, six patients from five families were identified with homozygous or compound heterozygous variants in SLC6A5 gene. The seventh patient was identified with a heterozygous variant in the same gene. There is also functional evidence available for the variants, showing that they result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.
The SLC6A5 gene encodes the Sodium- and chloride-dependent glycine transporter 2 (GlyT2), a membrane protein responsible for re-uptake of glycine in the spinal cord and brainstem.

PMID:22753417 (2012) reported the identification of a new dominant SLC6A5 variant (p.Tyr705Cys) via single gene sequencing in eight individuals from three families in two cohorts of hyperekplexia patients. As well as classical hyperekplexia symptoms, certain individuals exhibited abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. This may be due to a complex phenotype caused by the variant or to the presence of additional unknown variants. There is also functional evidence available for this variant.

Both monoallelic and biallelic variants are associated with hyperekplexia 3 (MIM #614618) in OMIM (last accessed 23 April 2026). In addition, biallelic variants are associated with hyperekplexia 3 (MONDO:0013827) with 'Definitive' rating by General Inborn Errors of Metabolism GCEP in ClinGen.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v7.23 SLC6A5 Achchuthan Shanmugasundram Classified gene: SLC6A5 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v7.23 SLC6A5 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants with hyperekplexia. As reviewed by Hannah Robinson, other hyperekplexia-causing genes (e.g. GLRA1 & GLRB) are rated green on this panel. Hence, this gene should be promoted to green rating in the next update.
Childhood onset dystonia, chorea or related movement disorder v7.23 SLC6A5 Achchuthan Shanmugasundram Gene: slc6a5 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v7.22 SLC6A5 Achchuthan Shanmugasundram Phenotypes for gene: SLC6A5 were changed from Hyperekplexia 3, 614618 to Hyperekplexia 3, OMIM:614618; hyperekplexia 3, MONDO:0013827
Childhood onset dystonia, chorea or related movement disorder v7.21 SLC6A5 Achchuthan Shanmugasundram Publications for gene: SLC6A5 were set to 16751771
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Achchuthan Shanmugasundram Tag Q2_26_NHS_review tag was added to gene: SLC6A5.
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: SLC6A5.
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Achchuthan Shanmugasundram edited their review of gene: SLC6A5: Changed publications to: 16751771, 22753417
Childhood onset dystonia, chorea or related movement disorder v7.20 SLC6A5 Achchuthan Shanmugasundram reviewed gene: SLC6A5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperekplexia 3, OMIM:614618, hyperekplexia 3, MONDO:0013827; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v5.73 USP48 Ida Ertmanska Added comment: Comment on phenotypes: OMIM phenotype updated 23rd Apr 2026.
Monogenic hearing loss v5.73 USP48 Ida Ertmanska Phenotypes for gene: USP48 were changed from non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497 to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497; Deafness, autosomal dominant 85, OMIM:620227
Hereditary ataxia with onset in adulthood v8.30 MFN2 Ida Ertmanska reviewed gene: MFN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 41402974, 38170145, 35418194; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260, Hereditary motor and sensory neuropathy VIA, OMIM:601152; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy and identified with biallelic POPDC2 variants. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy and identified with biallelic POPDC2 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Progressive cardiac conduction disease v2.15 POPDC2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are five unrelated families reported with cardiac conduction disease. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are five unrelated families reported with cardiac conduction disease and with biallelic POPDC2 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy and identified with biallelic POPDC2 variants. Hence, this gene can be promoted to green rating in the next GMS update.
Progressive cardiac conduction disease v2.15 POPDC2 Achchuthan Shanmugasundram Classified gene: POPDC2 as Amber List (moderate evidence)
Progressive cardiac conduction disease v2.15 POPDC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated families reported with cardiac conduction disease. Hence, this gene can be promoted to green rating in the next GMS update.
Progressive cardiac conduction disease v2.15 POPDC2 Achchuthan Shanmugasundram Gene: popdc2 has been classified as Amber List (Moderate Evidence).
Progressive cardiac conduction disease v2.14 POPDC2 Achchuthan Shanmugasundram gene: POPDC2 was added
gene: POPDC2 was added to Progressive cardiac conduction disease. Sources: Literature
Q2_26_promote_green tags were added to gene: POPDC2.
Mode of inheritance for gene: POPDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POPDC2 were set to 40409267; 41456958
Phenotypes for gene: POPDC2 were set to Cardiac conduction disease with or without cardiomyopathy 2, OMIM:621367; cardiac conduction disease with or without cardiomyopathy 2, MONDO:0700389
Review for gene: POPDC2 was set to GREEN
Added comment: PMID:40409267 (2025) reported the identification of biallelic variants in POPDC2 gene in six patients from four families presenting with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy. Modelling and electrophysiological studies suggested effects of identified POPDC2 variants on cAMP binding and TREK-1 current.

PMID:41456958 (2026) reported the identification of a novel homozygous POPDC2 variant in a patient presenting with early-onset cardiac conduction disease and hypertrophic cardiomyopathy.

This gene has been associated with relevant phenotype in OMIM (MIM #621367, record last accessed on 22 April 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram Classified gene: POPDC2 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated individuals reported with both cardiac conduction disease and hypertrophic cardiomyopathy. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.102 POPDC2 Achchuthan Shanmugasundram Gene: popdc2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v7.101 POPDC2 Achchuthan Shanmugasundram Phenotypes for gene: POPDC2 were changed from cardiac conduction defects and hypertrophic cardiomyopathy to Cardiac conduction disease with or without cardiomyopathy 2, OMIM:621367; cardiac conduction disease with or without cardiomyopathy 2, MONDO:0700389
Paediatric or syndromic cardiomyopathy v7.100 POPDC2 Achchuthan Shanmugasundram Publications for gene: POPDC2 were set to PMID: 40409267
Paediatric or syndromic cardiomyopathy v7.99 POPDC2 Achchuthan Shanmugasundram edited their review of gene: POPDC2: Changed phenotypes to: Cardiac conduction disease with or without cardiomyopathy 2, OMIM:621367, cardiac conduction disease with or without cardiomyopathy 2, MONDO:0700389
Paediatric or syndromic cardiomyopathy v7.99 POPDC2 Achchuthan Shanmugasundram Tag Q2_26_promote_green tag was added to gene: POPDC2.
Paediatric or syndromic cardiomyopathy v7.99 POPDC2 Achchuthan Shanmugasundram reviewed gene: POPDC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 40409267, 41456958; Phenotypes: Cardiac conduction disease with or without cardiomyopathy 2, OMIM:621367; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic short stature v1.36 VPS50 Ida Ertmanska Tag curated_removed tag was added to gene: VPS50.
Monogenic short stature v1.36 VPS50 Ida Ertmanska Tag Q2_26_promote_green was removed from gene: VPS50.
Monogenic short stature v1.36 VPS50 Ida Ertmanska Classified gene: VPS50 as No list
Monogenic short stature v1.36 VPS50 Ida Ertmanska Gene: vps50 has been removed from the panel.
Monogenic short stature v1.35 VPS50 Ida Ertmanska Classified gene: VPS50 as Red List (low evidence)
Monogenic short stature v1.35 VPS50 Ida Ertmanska Added comment: Comment on list classification: As per current Test Directory criteria for this panel, presence of microcephaly in an individual excludes R453 Monogenic short stature testing. While there are 3 individuals reported with short stature and biallelic VPS50 variants, including two individuals with more than -2 Z, all 3 had microcephaly as well. Hence, this gene should be Grey and tagged curated_removed on this panel.
Monogenic short stature v1.35 VPS50 Ida Ertmanska Gene: vps50 has been classified as Red List (Low Evidence).
Monogenic short stature v1.34 VPS50 Ida Ertmanska edited their review of gene: VPS50: Changed rating: RED
Cholestasis v3.24 VPS50 Ida Ertmanska commented on gene: VPS50: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Monogenic short stature v1.34 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Her height was 77cm at 18 months (-1.69 Z). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Monogenic short stature v1.34 VPS50 Ida Ertmanska Deleted their comment
Cholestasis v3.24 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Her height was 77cm at 18 months (-1.69 Z). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.24 VPS50 Ida Ertmanska Deleted their comment
Monogenic short stature v1.34 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Monogenic short stature v1.33 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Monogenic short stature v1.32 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Intellectual disability v9.397 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Intellectual disability v9.397 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Intellectual disability v9.396 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Intellectual disability v9.395 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Monogenic short stature v1.32 VPS50 Ida Ertmanska commented on gene: VPS50: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Intellectual disability v9.395 VPS50 Ida Ertmanska commented on gene: VPS50: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Monogenic short stature v1.32 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v9.395 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v8.192 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Early onset or syndromic epilepsy v8.191 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Early onset or syndromic epilepsy v8.191 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Early onset or syndromic epilepsy v8.190 VPS50 Ida Ertmanska Classified gene: VPS50 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.190 VPS50 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Early onset or syndromic epilepsy v8.190 VPS50 Ida Ertmanska Gene: vps50 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.189 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Early onset or syndromic epilepsy v8.189 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v8.51 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Severe microcephaly v8.51 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Severe microcephaly v8.50 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Severe microcephaly v8.49 VPS50 Ida Ertmanska Classified gene: VPS50 as Amber List (moderate evidence)
Severe microcephaly v8.49 VPS50 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Severe microcephaly v8.49 VPS50 Ida Ertmanska Gene: vps50 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v8.48 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Severe microcephaly v8.48 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v7.58 VPS50 Ida Ertmanska commented on gene: VPS50: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Malformations of cortical development v7.58 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Malformations of cortical development v7.58 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Malformations of cortical development v7.57 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Malformations of cortical development v7.56 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Malformations of cortical development v7.56 VPS50 Ida Ertmanska edited their review of gene: VPS50: Changed rating: GREEN; Changed publications to: 38876772; Changed phenotypes to: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v3.24 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birth = 34.5 cm (Z score +0.29). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Malformations of cortical development v7.56 VPS50 Ida Ertmanska commented on gene: VPS50
Cholestasis v3.24 VPS50 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Cholestasis v3.24 VPS50 Ida Ertmanska Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Cholestasis v3.23 VPS50 Ida Ertmanska Classified gene: VPS50 as Amber List (moderate evidence)
Cholestasis v3.23 VPS50 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Cholestasis v3.23 VPS50 Ida Ertmanska Gene: vps50 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.22 VPS50 Ida Ertmanska Tag watchlist was removed from gene: VPS50.
Tag Q2_26_promote_green tag was added to gene: VPS50.
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birth = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birth = 34.5 cm (Z score +0.29). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birth = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Intellectual disability v9.395 WDR91 Ida Ertmanska Phenotypes for gene: WDR91 were changed from Abnormal brain morphology, HP:0012443 to Abnormal brain morphology, HP:0012443; Neurodevelopmental delay, HP:0012758
Intellectual disability v9.394 WDR91 Ida Ertmanska Classified gene: WDR91 as Amber List (moderate evidence)
Intellectual disability v9.394 WDR91 Ida Ertmanska Added comment: Comment on list classification: There are 2 unrelated individuals reported in literature with biallelic WDR91 variants and syndromic neurodevelopmental delay. Animal models support the role of WDR91 in neuronal development and function. Mice lacking Wdr91 exhibited behavioural defects. Hence, this gene should be promoted to Green at the next update.
Intellectual disability v9.394 WDR91 Ida Ertmanska Gene: wdr91 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v7.56 WDR91 Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic WDR91 variants and brain malformations (1 case non-specific; 2 cases with findings such as CC agenesis, lissencephaly, cerebral hemisphere hypoplasia). Animal models support the role of WDR91 in neuronal development and function. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic WDR91 variants and cortical malformations (1 case non-specific; 2 cases with findings such as CC agenesis, lissencephaly, cerebral hemisphere hypoplasia). Animal models support the role of WDR91 in neuronal development and function. Hence, this gene should be promoted to Green at the next update.
Malformations of cortical development v7.56 WDR91 Ida Ertmanska Classified gene: WDR91 as Amber List (moderate evidence)
Malformations of cortical development v7.56 WDR91 Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic WDR91 variants and brain malformations (1 case non-specific; 2 cases with findings such as CC agenesis, lissencephaly, cerebral hemisphere hypoplasia). Animal models support the role of WDR91 in neuronal development and function. Hence, this gene should be promoted to Green at the next update.
Malformations of cortical development v7.56 WDR91 Ida Ertmanska Gene: wdr91 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.393 WDR91 Ida Ertmanska gene: WDR91 was added
gene: WDR91 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: WDR91.
Mode of inheritance for gene: WDR91 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR91 were set to 32732226; 34028500; 34791078; 38041506; 40550703
Phenotypes for gene: WDR91 were set to Abnormal brain morphology, HP:0012443
Review for gene: WDR91 was set to GREEN
Added comment: PMID: 32732226 Lefebvre et al., 2021
Homozygous variant WDR91 c.240C>G, p.(Tyr80*) detected in a male fetus with hygroma, macrocephaly, abnormal ears, cerebellar hypoplasia, and hydrocephaly. Concordant segregation among 4 affected fetus, 2 healthy sibs, and both parents.

PMID: 34791078 Kurul et al., 2022
Large study, trio exome seq of consanguineous families with neurogenetic diseases. FMAL006_01 - female patient with 'brain malformation' was homozygous for WDR91 c.1395+1G>A. No more details provided.

PMID: 38041506 Rosina et al., 2024
Case 75 - male, 3yrs 5mo, homozygous for WDR91 NM_014149.4:c.511+1A>G. Phenotype: severe developmental delay, microcephaly, severe microlissencephaly, agenesis of corpus callosum, epilepsy, spastic tetraparesis, laryngomalacia, bicuspid aortic valve, congenital hip dislocation, growth retardation, dysmorphisms.

PMID: 40550703 Marinakis et al., 2026
Consanguineous Syrian family. Proband (4mo female) presented with severe microcephaly, dysmorphic features, organomegaly, early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Brain MRI revealed bilateral cerebral hemisphere hypoplasia with incomplete sulcation, agenesis of the corpus callosum, suspected bilateral periventricular heterotopias. WES identified a homozygous splice site variant, WDR91 NM_014149.4: c.1395+1G>A (same as in PMID: 34791078, but NOT the same patient).

Functional: PMID: 34028500 Xing et al., 2021 - Mice lacking Wdr91 specifically in the central nervous system exhibited behavioral defects and marked neuronal loss in the cerebral and cerebellar cortices. At a cellular level, Wdr91 deficiency caused dysfunction of lysosomes, leading to accumulation of autophagic cargoes in mouse neurons.

WDR91 is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Malformations of cortical development v7.55 WDR91 Ida Ertmanska gene: WDR91 was added
gene: WDR91 was added to Malformations of cortical development. Sources: Literature
Q2_26_promote_green tags were added to gene: WDR91.
Mode of inheritance for gene: WDR91 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR91 were set to 32732226; 34028500; 34791078; 38041506; 40550703
Phenotypes for gene: WDR91 were set to Abnormal brain morphology, HP:0012443
Review for gene: WDR91 was set to GREEN
Added comment: PMID: 32732226 Lefebvre et al., 2021
Homozygous variant WDR91 c.240C>G, p.(Tyr80*) detected in a male fetus with hygroma, macrocephaly, abnormal ears, cerebellar hypoplasia, and hydrocephaly. Concordant segregation among 4 affected fetus, 2 healthy sibs, and both parents.

PMID: 34791078 Kurul et al., 2022
Large study, trio exome seq of consanguineous families with neurogenetic diseases. FMAL006_01 - female patient with 'brain malformation' was homozygous for WDR91 c.1395+1G>A. No more details provided.

PMID: 38041506 Rosina et al., 2024
Case 75 - male, 3yrs 5mo, homozygous for WDR91 NM_014149.4:c.511+1A>G. Phenotype: severe developmental delay, microcephaly, severe microlissencephaly, agenesis of corpus callosum, epilepsy, spastic tetraparesis, laryngomalacia, bicuspid aortic valve, congenital hip dislocation, growth retardation, dysmorphisms.

PMID: 40550703 Marinakis et al., 2026
Consanguineous Syrian family. Proband (4mo female) presented with severe microcephaly, dysmorphic features, organomegaly, early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Brain MRI revealed bilateral cerebral hemisphere hypoplasia with incomplete sulcation, agenesis of the corpus callosum, suspected bilateral periventricular heterotopias. WES identified a homozygous splice site variant, WDR91 NM_014149.4: c.1395+1G>A (same as in PMID: 34791078, but NOT the same patient).

Functional: PMID: 34028500 Xing et al., 2021 - Mice lacking Wdr91 specifically in the central nervous system exhibited behavioral defects and marked neuronal loss in the cerebral and cerebellar cortices. At a cellular level, Wdr91 deficiency caused dysfunction of lysosomes, leading to accumulation of autophagic cargoes in mouse neurons.

WDR91 is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Early onset or syndromic epilepsy v8.189 ISCA-46297-Loss Arina Puzriakova edited their review of Region: ISCA-46297-Loss: Changed rating: RED
Intellectual disability v9.392 ISCA-46297-Loss Arina Puzriakova edited their review of Region: ISCA-46297-Loss: Changed rating: RED
Monogenic hearing loss v5.72 ISCA-46297-Loss Arina Puzriakova Phenotypes for Region: ISCA-46297-Loss were changed from to Autosomal recessive deafness-22
Monogenic hearing loss v5.71 ISCA-46297-Loss Arina Puzriakova Publications for Region: ISCA-46297-Loss were set to 31204719; 19888295; 20301607; 25719193; 30836598
Monogenic hearing loss v5.70 ISCA-46297-Loss Arina Puzriakova commented on Region: ISCA-46297-Loss: Homozygous distal 16p12.2 deletions, encompassing the OTOA gene, are associated with autosomal recessive deafness-22 (PMID: 19888295; 31204719; 39916398)
Early onset or syndromic epilepsy v8.189 ISCA-46297-Loss Arina Puzriakova Tag Q2_26_demote_red tag was added to Region: ISCA-46297-Loss.
Intellectual disability v9.392 ISCA-46297-Loss Arina Puzriakova Tag Q2_26_demote_red tag was added to Region: ISCA-46297-Loss.
Early onset or syndromic epilepsy v8.189 ISCA-46297-Loss Arina Puzriakova commented on Region: ISCA-46297-Loss: This region should be demoted from green to red at the next GMS panel update. ClinGen summary states that heterozygous deletions of this region are not dosage sensitive (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46297).

Homozygous distal 16p12.2 deletions, encompassing the OTOA gene, are associated with autosomal recessive deafness-22 (PMID: 19888295; 31204719; 39916398)

16p12.2 proximal deletions (distinct genomic coordinates) have been linked to neurodevelopmental phenotypes (PMID: 20154674; 25719193; 30836598; 30190612), however the evidence is classified as 'emerging' in ClinGen and is insufficient to add to diagnostic GMS panels at this time (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37409).
Intellectual disability v9.392 ISCA-46297-Loss Arina Puzriakova commented on Region: ISCA-46297-Loss: This region should be demoted from green to red at the next GMS panel update. ClinGen summary states that heterozygous deletions of this region are not dosage sensitive (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46297).

Homozygous distal 16p12.2 deletions, encompassing the OTOA gene, are associated with autosomal recessive deafness-22 (PMID: 19888295; 31204719; 39916398)

16p12.2 proximal deletions (distinct genomic coordinates) have been linked to neurodevelopmental phenotypes (PMID: 20154674; 25719193; 30836598; 30190612), however the evidence is classified as 'emerging' in ClinGen and is insufficient to add to diagnostic GMS panels at this time (https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37409).
Fetal anomalies v6.192 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental delay, dysmorphic features, brain structural abnormalities, growth restriction, hypotonia, microcephaly; Luo-Agrawal neurodevelopmental syndrome, OMIM:621552 neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental delay, dysmorphic features, brain structural abnormalities, growth restriction, hypotonia, microcephaly; Luo-Agrawal neurodevelopmental syndrome, OMIM:621552; neurodevelopmental disorder, MONDO:0700092
Fetal anomalies v6.191 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental delay, dysmorphic features, brain structural abnormalities, growth restriction, hypotonia, microcephaly; neurodevelopmental disorder, MONDO:0700092 to neurodevelopmental delay, dysmorphic features, brain structural abnormalities, growth restriction, hypotonia, microcephaly; Luo-Agrawal neurodevelopmental syndrome, OMIM:621552 neurodevelopmental disorder, MONDO:0700092
Ataxia and cerebellar anomalies - narrow panel v8.82 WSB2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Ataxia and cerebellar anomalies - narrow panel v8.82 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental disorder, MONDO:0700092 to Luo-Agrawal neurodevelopmental syndrome, OMIM:621552; neurodevelopmental disorder, MONDO:0700092
Intellectual disability v9.392 WSB2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Intellectual disability v9.392 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental disorder, MONDO:0700092 to Luo-Agrawal neurodevelopmental syndrome, OMIM:621552; neurodevelopmental disorder, MONDO:0700092
Early onset or syndromic epilepsy v8.189 WSB2 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Early onset or syndromic epilepsy v8.189 WSB2 Ida Ertmanska Phenotypes for gene: WSB2 were changed from neurodevelopmental disorder, MONDO:0700092 to Luo-Agrawal neurodevelopmental syndrome, OMIM:621552; neurodevelopmental disorder, MONDO:0700092
Severe microcephaly v8.48 ZNF668 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Severe microcephaly v8.48 ZNF668 Ida Ertmanska Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194 neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MONDO:0859350
Monogenic short stature v1.32 ZNF668 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Monogenic short stature v1.32 ZNF668 Ida Ertmanska Phenotypes for gene: ZNF668 were changed from Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194 to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194 neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MONDO:0859350
Intellectual disability v9.391 ZNF668 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Intellectual disability v9.391 ZNF668 Ida Ertmanska Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194; neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MONDO:0859350
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.22 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.22 VPS50 Ida Ertmanska Publications for gene: VPS50 were set to 34037727
Cholestasis v3.21 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.21 VPS50 Ida Ertmanska changed review comment from: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).; to: 3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv;
93232033_93659940del), maternally inherited. The deletion also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. No microcephaly (OFC at birht = 34.5 cm (Z score +0.29)
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Cholestasis v3.21 VPS50 Ida Ertmanska reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.190 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Fetal anomalies v6.190 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from Congenital disorder of glycosylation to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Early onset or syndromic epilepsy v8.188 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Early onset or syndromic epilepsy v8.188 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Intellectual disability v9.390 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Intellectual disability v9.390 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Likely inborn error of metabolism v8.111 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Likely inborn error of metabolism v8.111 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Severe microcephaly v8.47 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Severe microcephaly v8.47 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Congenital disorders of glycosylation v7.17 UGGT1 Ida Ertmanska Added comment: Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Congenital disorders of glycosylation v7.17 UGGT1 Ida Ertmanska Phenotypes for gene: UGGT1 were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type IICC, OMIM:621381; congenital disorder of glycosylation, type IIcc, MONDO:0980705
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with pituitary involvement. Patients exhibited impaired pituitary function. Pituitary anomalies e.g., pituitary hypoplasia / stalk interruption, were seen on MRI in 5 different families. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Pituitary hormone deficiency v4.6 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v4.5 TTC26 Ida Ertmanska changed review comment from: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who exhibited bilateral small kidney size and abnormal kidney function, cryptorchidism and short penis, optic atrophy, pituitary anomalies, hexadactyly, congenital cardiac defect, thyroid dysfunction, partial hypopituitarism, and other features (though no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature; to: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who exhibited bilateral small kidney size and abnormal kidney function, cryptorchidism and short penis, optic atrophy, pituitary anomalies (including missing pituitary stalk on imaging), hexadactyly, congenital cardiac defect, thyroid dysfunction, partial hypopituitarism, and other features (though no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Pituitary hormone deficiency v4.5 TTC26 Ida Ertmanska changed review comment from: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature; to: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who exhibited bilateral small kidney size and abnormal kidney function, cryptorchidism and short penis, optic atrophy, pituitary anomalies, hexadactyly, congenital cardiac defect, thyroid dysfunction, partial hypopituitarism, and other features (though no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Pituitary hormone deficiency v4.5 TTC26 Ida Ertmanska changed review comment from: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature; to: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI (3/4).

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Rare multisystem ciliopathy disorders v1.182 TTC26 Ida Ertmanska Phenotypes for gene: TTC26 were changed from Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Rare multisystem ciliopathy disorders v1.181 TTC26 Ida Ertmanska Classified gene: TTC26 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.181 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Green List (High Evidence).
Limb disorders v7.33 TTC26 Ida Ertmanska changed review comment from: Comment on list classification: here are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with limb involvement. Patients consistently presented with polydactyly. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with limb involvement. Patients consistently presented with polydactyly. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Limb disorders v7.33 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Limb disorders v7.33 TTC26 Ida Ertmanska Added comment: Comment on list classification: here are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with limb involvement. Patients consistently presented with polydactyly. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Limb disorders v7.33 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Cholestasis v3.21 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Cholestasis v3.21 TTC26 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with biliary involvement. Patients exhibited severe early-onset cholestasis, in some cases leading to liver transplants and early lethality. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Cholestasis v3.21 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with neurological involvement. Patients exhibited optic atrophy and pituitary hypoplasia seen on imaging. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Neurological ciliopathies v6.21 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.23 TTC26 Ida Ertmanska Classified gene: TTC26 as Amber List (moderate evidence)
Renal ciliopathies v4.23 TTC26 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported in literature with biallelic TTC26 variants and a multisystem ciliopathy with renal involvement. Patients exhibit impaired renal function and abnormal kidney morphology. Animal models support function of TTC26 in ciliogenesis and ciliary function. Hence, this gene should be promoted to Green at the next update.
Renal ciliopathies v4.23 TTC26 Ida Ertmanska Gene: ttc26 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.22 TTC26 Ida Ertmanska changed review comment from: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature; to: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who exhibited bilateral small kidney size and abnormal kidney function, cryptorchidism and short penis, optic atrophy, pituitary anomalies, hexadactyly, congenital cardiac defect, thyroid dysfunction, partial hypopituitarism, and other features (though no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Cholestasis v3.20 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Cholestasis. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Pituitary hormone deficiency v4.5 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Pituitary hormone deficiency. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Renal ciliopathies v4.22 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Renal ciliopathies. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Limb disorders v7.32 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Limb disorders. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Neurological ciliopathies v6.20 TTC26 Ida Ertmanska gene: TTC26 was added
gene: TTC26 was added to Neurological ciliopathies. Sources: Literature
Q2_26_promote_green tags were added to gene: TTC26.
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 31595528; 32617964; 34177428; 38135897; 39514123
Phenotypes for gene: TTC26 were set to Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534; biliary, renal, neurologic, and skeletal syndrome, MONDO:0859191
Review for gene: TTC26 was set to GREEN
Added comment: PMID: 31595528 Shaheen et al., 2020
Report of seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one, required liver transplant in two cases). Other features: polydactyly (5/7), echogenic kidneys with impaired renal function (5/7), variable cardiac anomalies (5/7).
TTC26 variants detected: NM_024926.4: c.788A>G, p.Asn263Ser (4 patients, shared haplotype); c.1331C>T, p.Pro444Leu (1 patient, and c.4-1G>C (2 patients).

PMID: 32617964 David et al., 2020
Four patients from two apparently unrelated consanguineous Bedouin families with ciliopathy due to a homozygous TTC26 c.695A>G p.Asn232Ser mutation. Patients had dysmorphic features, early-onset cholestatic jaundice (4/4), pituitary hormone deficiency (2/4), postaxial polydactyly (3/4), ectopic / absent neurohypophysis (posterior lobe of the pituitary gland) on brain MRI.

PMID: 34177428 Alfadhel et al., 2021
Nonconsanguineous Saudi family. The female proband exhibited cholestasis, cystic dilatation of intrahepatic biliary ducts, diabetes insipidus, dysmorphic facial features, optic atrophy, hydrocephalus, aqueductal stenosis, hyperextensible knee joints, bilateral knee dislocation, polydactyly, and syndactyly. Brain MRI showed pituitary hypoplasia. She died at 15 months of age.
WGS + Sanger sequencing revealed a homozygous TTC26 variant (c.4-1G>C; NM_024926.3).

PMID: 38135897 Papingi et al., 2024
Male patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, unilateral hearing impairment, a congenital heart defect, and a bilateral lip-palate cleft. He was homozygous for TTC26 c.1006-5T> C. Parents are first degree-cousins, Afghan ancestry.

PMID: 39514123 Yang et al., 2025
Chinese case of BRENS syndrome who presented with kidney, neurological, skeletal, and other features (no biliary involvement). 3 TTC26 variant detected: c.1069+5G>A inherited from the mother and c.511A>G (p.Ile171Val) and c.1099T>C (p.Ser367Pro) from the father.

Functional evidence:
PMID: 24596149 Ishikawa et al., 2014 - Knockdown of ttc26 in zebrafish embryos or mutation of Dyf13 (TTC26 ortholog) in C. reinhardtii produced short cilia with abnormal motility.

TTC26 is associated with AR Biliary, renal, neurologic, and skeletal syndrome, OMIM:619534 (OMIM accessed 22nd Apr 2026).
Sources: Literature
Intellectual disability v9.389 PGBD5 Karen Stals gene: PGBD5 was added
gene: PGBD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PGBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGBD5 were set to PMID: 41533792
Phenotypes for gene: PGBD5 were set to Seizures; global developmental delay; spasticity; hypotonia
Penetrance for gene: PGBD5 were set to Complete
Review for gene: PGBD5 was set to GREEN
gene: PGBD5 was marked as current diagnostic
Added comment: Zapater et al. 2026 PMID:41533792 report 5 families with homozygous loss of function variants in PGBD5 co-segregating in two affected siblings in each family (variants identified via whole exome sequencing). Authors show that PGBD5 contributes to normal brain development in mice and humans.
Sources: Literature
Early onset or syndromic epilepsy v8.187 PGBD5 Karen Stals gene: PGBD5 was added
gene: PGBD5 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: PGBD5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGBD5 were set to PMID: 41533792
Phenotypes for gene: PGBD5 were set to Seizures; global developmental delay; spasticity; hypotonia
Penetrance for gene: PGBD5 were set to Complete
Review for gene: PGBD5 was set to GREEN
gene: PGBD5 was marked as current diagnostic
Added comment: Zapater et al. 2026 PMID:41533792 report 5 families with homozygous loss of function variants in PGBD5 co-segregating in two affected siblings in each family (variants identified via whole exome sequencing). Authors show that PGBD5 contributes to normal brain development in mice and humans.
Sources: Literature
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TMEM17.
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Classified gene: TMEM17 as Amber List (moderate evidence)
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Added comment: Comment on list classification: There are at least 9 unrelated individuals (3 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and evidence of a multisystem ciliopathy (molar tooth sign, features supporting a diagnosis of Meckel syndrome, Joubert syndrome). More than 3 unrelated individuals had polycystic kidneys, as well as other renal findings. Hence, this gene should be promoted to Green at the next update.
Cystic kidney disease v8.15 TMEM17 Ida Ertmanska Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.21 TMEM17 Ida Ertmanska Classified gene: TMEM17 as Amber List (moderate evidence)
Renal ciliopathies v4.21 TMEM17 Ida Ertmanska Added comment: Comment on list classification: There are at least 9 unrelated individuals (3 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and evidence of a multisystem ciliopathy (molar tooth sign, features supporting a diagnosis of Meckel syndrome, Joubert syndrome). More than 3 unrelated individuals had renal finding such as renal dysplasia, polycystic kidneys, and enlarged, echogenic kidneys. Hence, this gene should be promoted to Green at the next update.
Renal ciliopathies v4.21 TMEM17 Ida Ertmanska Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v4.20 TMEM17 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TMEM17.
Neurological ciliopathies v6.19 TMEM17 Ida Ertmanska Classified gene: TMEM17 as Amber List (moderate evidence)
Neurological ciliopathies v6.19 TMEM17 Ida Ertmanska Added comment: Comment on list classification: There are at least 9 unrelated individuals (3 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and evidence of a multisystem ciliopathy (molar tooth sign, features supporting a diagnosis of Meckel syndrome, Joubert syndrome). Hence, this gene should be promoted to Green at the next update.
Neurological ciliopathies v6.19 TMEM17 Ida Ertmanska Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v6.18 TMEM17 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TMEM17.
Limb disorders v7.31 TMEM17 Ida Ertmanska Classified gene: TMEM17 as Amber List (moderate evidence)
Limb disorders v7.31 TMEM17 Ida Ertmanska Added comment: Comment on list classification: There are at least 8 unrelated individuals (2 surviving individuals and 6 fetal cases) reported with biallelic TMEM17 variants and polydactyly. Hence, this gene should be promoted to Green on Limb disorders at the next update.
Limb disorders v7.31 TMEM17 Ida Ertmanska Gene: tmem17 has been classified as Amber List (Moderate Evidence).
Limb disorders v7.30 TMEM17 Ida Ertmanska Tag Q2_26_promote_green tag was added to gene: TMEM17.
Renal ciliopathies v4.20 TMEM17 Ida Ertmanska gene: TMEM17 was added
gene: TMEM17 was added to Renal ciliopathies. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827
Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772
Review for gene: TMEM17 was set to GREEN
Added comment: PMID: 26982032 Li et al., 2016
Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother.

PMID: 32055034 Shamseldin et al., 2020
Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome.

PMID: 40841990 Boutaud et al., 2025
Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy).

PMID: 41054827 Pardo et al., 2025
Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality.

This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Neurological ciliopathies v6.18 TMEM17 Ida Ertmanska gene: TMEM17 was added
gene: TMEM17 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827
Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772
Review for gene: TMEM17 was set to GREEN
Added comment: PMID: 26982032 Li et al., 2016
Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother.

PMID: 32055034 Shamseldin et al., 2020
Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome.

PMID: 40841990 Boutaud et al., 2025
Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy).

PMID: 41054827 Pardo et al., 2025
Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality.

This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Cystic kidney disease v8.14 TMEM17 Ida Ertmanska gene: TMEM17 was added
gene: TMEM17 was added to Cystic kidney disease. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827
Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772
Review for gene: TMEM17 was set to GREEN
Added comment: PMID: 26982032 Li et al., 2016
Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother.

PMID: 32055034 Shamseldin et al., 2020
Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome.

PMID: 40841990 Boutaud et al., 2025
Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy).

PMID: 41054827 Pardo et al., 2025
Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality.

This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Limb disorders v7.30 TMEM17 Ida Ertmanska gene: TMEM17 was added
gene: TMEM17 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: TMEM17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM17 were set to 26982032; 32055034; 40841990; 41054827
Phenotypes for gene: TMEM17 were set to Meckel syndrome, MONDO:0018921; orofaciodigital syndrome type 6, MONDO:0010176; Joubert syndrome, MONDO:0018772
Review for gene: TMEM17 was set to GREEN
Added comment: PMID: 26982032 Li et al., 2016
Homozygous missense mutation reported in TMEM17 (p.Asn102Lys) in two siblings (both male, 20 yrs and 36yrs old whose clinical profile is consistent with Oral-Facial-Digital type 6 syndrome. Both patients had polydactyly, psychomotor delay; cerebellar hypoplasia and molar tooth sign also noted on brain imaging (see S2 table). Fibroblasts from a TMEM17-mutated sibling displayed a much reduced ability to form cilia compared to cells from the healthy heterozygous mother.

PMID: 32055034 Shamseldin et al., 2020
Homozygous variant NM_198276:c.302G > T; p.Gly101Val detected in a child with Joubert syndrome.

PMID: 40841990 Boutaud et al., 2025
Report of two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts. Exome sequencing identified a founder homozygous missense variant c.280C>T, p.(Arg94Trp) in TMEM17. Both diagnosed with Meckel syndrome (severe ciliopathy).

PMID: 41054827 Pardo et al., 2025
Four unrelated patients were identified with a clinical diagnosis of Meckel-Gruber syndrome (MGS) - a severe, lethal ciliopathy - and novel homozygous TMEM17 variants: NM_198276.3 c.4del p.(Glu2Serfs*58); c.366dup p.(Pro123Thrfs*9); and c.368C>G p.(Pro123Arg). Severe prenatal phenotype: encephalocele, polycystic kidney dysplasia, and polydactyly, leading to early lethality.

This gene is not yet associated with a phenotype in OMIM, G2P, or ClinGen (accessed 22nd Apr 2026).
Sources: Literature
Malformations of cortical development v7.54 SNAPIN Ida Ertmanska Classified gene: SNAPIN as Amber List (moderate evidence)
Malformations of cortical development v7.54 SNAPIN Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 3 unrelated families reported with biallelic SNAPIN variants and CC agenesis. Hence, this gene should be promoted to Green at the next update.
Malformations of cortical development v7.54 SNAPIN Ida Ertmanska Gene: snapin has been classified as Amber List (Moderate Evidence).
Arthrogryposis v9.34 SNAPIN Ida Ertmanska Classified gene: SNAPIN as Amber List (moderate evidence)
Arthrogryposis v9.34 SNAPIN Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 3 unrelated families reported with biallelic SNAPIN variants and flexion contractures. Hence, this gene should be promoted to Green at the next update.
Arthrogryposis v9.34 SNAPIN Ida Ertmanska Gene: snapin has been classified as Amber List (Moderate Evidence).
Fetal anomalies v6.189 SNAPIN Ida Ertmanska Tag Q1_26_promote_green was removed from gene: SNAPIN.
Malformations of cortical development v7.53 SNAPIN Ida Ertmanska gene: SNAPIN was added
gene: SNAPIN was added to Malformations of cortical development. Sources: Literature
Q2_26_promote_green tags were added to gene: SNAPIN.
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Review for gene: SNAPIN was set to GREEN
Added comment: Review by Achchuthan Shanmugasundram (Genomics England Curator) copied from Ataxia and cerebellar anomalies - narrow panel.

PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Arthrogryposis v9.33 SNAPIN Ida Ertmanska gene: SNAPIN was added
gene: SNAPIN was added to Arthrogryposis. Sources: Literature
Q2_26_promote_green tags were added to gene: SNAPIN.
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393; neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, MONDO:0980710
Review for gene: SNAPIN was set to GREEN
Added comment: Review by Achchuthan Shanmugasundram (Genomics England Curator) copied from Ataxia and cerebellar anomalies - narrow panel.

PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). One of the foetuses had intrauterine demise at 26 weeks' gestation, and the other 3 pregnancies ended in termination. Brain abnormalities in the patients included ventriculomegaly (5/6), cerebellar hypoplasia/ atrophy (5/6) and corpus callosum agenesis (4/6). The other phenotypes included clubfeet (4/6), flexion contractures (4/6), microcephaly (3/6) and micrognathia/retrognathia (4/6).

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Intellectual disability v9.389 SKOR2 Ida Ertmanska Classified gene: SKOR2 as Amber List (moderate evidence)
Intellectual disability v9.389 SKOR2 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic SKOR2 variants and syndromic intellectual disability / developmental delay. Hence, this gene should be promoted to Green at the next update. Though the intellectual disability was generally mild, addition to this panel also ensures inclusion on R27 Paediatric disorders.
Intellectual disability v9.389 SKOR2 Ida Ertmanska Gene: skor2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v8.81 SKOR2 Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals with biallelic SKOR2 variants and childhood onset ataxia and /or evidence of cerebellar anomalies on MRI. Hence, this gene should be promoted to Green at the next update.; to: Comment on list classification: There are more than 3 unrelated individuals reported with biallelic SKOR2 variants and childhood onset ataxia and /or evidence of cerebellar anomalies on MRI. Hence, this gene should be promoted to Green at the next update.
Ataxia and cerebellar anomalies - narrow panel v8.81 SKOR2 Ida Ertmanska Classified gene: SKOR2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v8.81 SKOR2 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals with biallelic SKOR2 variants and childhood onset ataxia and /or evidence of cerebellar anomalies on MRI. Hence, this gene should be promoted to Green at the next update.
Ataxia and cerebellar anomalies - narrow panel v8.81 SKOR2 Ida Ertmanska Gene: skor2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.388 SKOR2 Ida Ertmanska gene: SKOR2 was added
gene: SKOR2 was added to Intellectual disability. Sources: Literature
Q2_26_promote_green tags were added to gene: SKOR2.
Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SKOR2 were set to 29997391; 40890458; 41821366
Phenotypes for gene: SKOR2 were set to Valence-Farazi cerebellar ataxia syndrome, OMIM: 621386; Valence-Farazi cerebellar ataxia syndrome, MONDO:0980707
Review for gene: SKOR2 was set to GREEN
Added comment: PMID: 29997391 Valence et al., 2019
Patient P15 - 10yo female, consanguineous Turkish parents; she presented with neonatal hypotonia and psychomotor delay; at age 10, she had scoliosis, nystagmus, mild ID, and a nonprogressive ataxia with ataxic gait. She was homozygous for SKOR2 variant NM_001278063.1: c.2750C>G; p.Ser917*. Cerebellar dysplasia seen on brain MRI.

PMID: 40890458 Farazi Fard et al., 2025
9 patients from 2 unrelated consanguineous Iranian families:
Family 1 - 8 affected individuals homozygous for SKOR2 c.374G>C, p.Arg125Pro variant; ataxia present in 6/8 individuals, cerebellar hypoplasia in 8/8. Other phenotypes: scoliosis (5/8), strabismus (4/8), and other more variable features.
Family 2 - affected 6yo female proband homozygous for SKOR2 c.1271_1274del, p.Lys424Argfs*71 variant; she had strabismus, hypotonia, cerebellar hypoplasia, and osteomalacia, but no ataxia reported.

PMID: 41821366 Abu-El-Haija et al., 2026 - Online ahead of print
Report of eight individuals from five unrelated families (from Iraq, Turkey, Pakistan, Morocco, and South East Asia) with biallelic variants in SKOR2 associated with a phenotypic spectrum of cerebellar hypoplasia, microcephaly, ataxia, developmental delays and intellectual disability. Disease with childhood-onset, consanguinity reported in 7/8 individuals. Ataxic gait noted in 4 individuals, generally delayed walking age (>2 years in 6 cases).
Intellectual disability was present in 5/5 individuals assessed (4 mild, IQ = 55-58, and 1 case with severe ID). Cerebellar anomalies noted on brain MRI in 6/6 patients, including cerebellar hypoplasia /atrophy in 4 cases. Scoliosis / kyphosis noted in 3 patients.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v8.80 SKOR2 Ida Ertmanska gene: SKOR2 was added
gene: SKOR2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q2_26_promote_green tags were added to gene: SKOR2.
Mode of inheritance for gene: SKOR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SKOR2 were set to 29997391; 40890458; 41821366
Phenotypes for gene: SKOR2 were set to Valence-Farazi cerebellar ataxia syndrome, OMIM: 621386; Valence-Farazi cerebellar ataxia syndrome, MONDO:0980707
Review for gene: SKOR2 was set to GREEN
Added comment: PMID: 29997391 Valence et al., 2019
Patient P15 - 10yo female, consanguineous Turkish parents; she presented with neonatal hypotonia and psychomotor delay; at age 10, she had scoliosis, nystagmus, mild ID, and a nonprogressive ataxia with ataxic gait. She was homozygous for SKOR2 variant NM_001278063.1: c.2750C>G; p.Ser917*. Cerebellar dysplasia seen on brain MRI.

PMID: 40890458 Farazi Fard et al., 2025
9 patients from 2 unrelated consanguineous Iranian families:
Family 1 - 8 affected individuals homozygous for SKOR2 c.374G>C, p.Arg125Pro variant; ataxia present in 6/8 individuals, cerebellar hypoplasia in 8/8. Other phenotypes: scoliosis (5/8), strabismus (4/8), and other more variable features.
Family 2 - affected 6yo female proband homozygous for SKOR2 c.1271_1274del, p.Lys424Argfs*71 variant; she had strabismus, hypotonia, cerebellar hypoplasia, and osteomalacia, but no ataxia reported.

PMID: 41821366 Abu-El-Haija et al., 2026 - Online ahead of print
Report of eight individuals from five unrelated families (from Iraq, Turkey, Pakistan, Morocco, and South East Asia) with biallelic variants in SKOR2 associated with a phenotypic spectrum of cerebellar hypoplasia, microcephaly, ataxia, developmental delays and intellectual disability. Disease with childhood-onset, consanguinity reported in 7/8 individuals. Ataxic gait noted in 4 individuals, generally delayed walking age (>2 years in 6 cases).
Intellectual disability was present in 5/5 individuals assessed (4 mild, IQ = 55-58, and 1 case with severe ID). Cerebellar anomalies noted on brain MRI in 6/6 patients, including cerebellar hypoplasia /atrophy in 4 cases. Scoliosis / kyphosis noted in 3 patients.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.51 RNU4-2 Ida Ertmanska Tag locus-type-rna-small-nuclear tag was added to gene: RNU4-2.
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia, arrhythmia, prolonged atrioventricular conduction. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia, arrhythmia, prolonged atrioventricular conduction. Heterozygous individuals in those families were asymptomatic. Mouse model is supportive of gene-disease association. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia / sinus arrest. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.; to: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia, arrhythmia, prolonged atrioventricular conduction. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska Classified gene: CACNA1D as Amber List (moderate evidence)
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and sinoatrial node dysfunction, resulting in sinus bradycardia / sinus arrest. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.
Cardiac arrhythmias - additional genes v3.11 CACNA1D Ida Ertmanska Gene: cacna1d has been classified as Amber List (Moderate Evidence).
Cardiac arrhythmias - additional genes v3.10 CACNA1D Ida Ertmanska gene: CACNA1D was added
gene: CACNA1D was added to Cardiac arrhythmias - additional genes. Sources: Literature
Q2_26_promote_green tags were added to gene: CACNA1D.
Mode of inheritance for gene: CACNA1D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1D were set to 21131953; 30498240; 30054272; 32747562
Phenotypes for gene: CACNA1D were set to Sinoatrial node dysfunction and deafness, OMIM:614896; sinoatrial node dysfunction and deafness, MONDO:0013960
Review for gene: CACNA1D was set to GREEN
Added comment: PMID: 21131953 Baig et al., 2011
Report of 2 consanguineous Pakistani families with bradycardia and congenital deafness, harbouring c.1208_1209insGGG (p.Gly403_Val404insGly) variant in CACNA1D.

PMID: 30498240 Liaqat et al., 2018
5 Pakistani families with Sinoatrial node dysfunction and deafness and homozygous CACNA1D variants- 1 family with p.(A376V), and 4 pedigrees with a founder variant p.(G403_V404insG) - common distant ancestor confirmed, same as families in PMID: 21131953.

PMID: 30054272 Garza-Lopez et al., 2018
Male proband of Arabic descent with moderate hearing impairment and intellectual disability, homozygous for CACNA1D c.1701G>C, p.Gln567His variant.

PMID: 32747562 Rayyan et al., 2020
Palestinian population study of 491 families with hearing loss. In 4 families, the same homozygous CACNA1D p.(Ala376Val) founder variant was found to be responsible for moderate hearing loss associated with cardiac anomalies, including prolonged atrioventricular conduction on an electrocardiogram.

Functional evidence: PMID: 10929716 Platzer et al., 2000 - Cacna1d-deficient mice were deaf due to degeneration of outer and inner hair cells. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia).

The link between CACNA1D and autosomal recessive sinoatrial node dysfunction and deafness has been classified as Moderate in ClinGen (Hearing loss GCEP, 2024).
Sources: Literature
Intellectual disability v9.387 CACNA1D Ida Ertmanska changed review comment from: Comment on mode of inheritance: Individuals reported with biallelic CACNA1D variants present with deafness and sinoatrial node dysfunction - no epilepsy or cognitive impairment (PMIDs: 21131953; 30498240; 30054272; 32747562). Monoallelic de novo variants result in primary aldosteronism, seizures, and neurologic abnormalities (more than 3 unrelated cases e.g., PMIDs: 23913001, 2847230; 37122292). The literature review by Alzahrani et al., 2023 (PMID: 37122292) states that intellectual disability affects 80% of patients, and seizures are present in 47% of cases of the dominant disorder. Hence, the mode of inheritance on Early onset or syndromic epilepsy should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.; to: Comment on mode of inheritance: Individuals reported with biallelic CACNA1D variants present with deafness and sinoatrial node dysfunction - no epilepsy or cognitive impairment (PMIDs: 21131953; 30498240; 30054272; 32747562). Monoallelic de novo variants result in primary aldosteronism, seizures, and neurologic abnormalities (more than 3 unrelated cases e.g., PMIDs: 23913001, 2847230; 37122292). The literature review by Alzahrani et al., 2023 (PMID: 37122292) states that intellectual disability affects 80% of patients, and seizures are present in 47% of cases of the dominant disorder. Hence, the mode of inheritance on Intellectual disability should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted at the next update.
Early onset or syndromic epilepsy v8.187 SHROOM4 Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated individuals with hemizygous SHROOM4 variants and isolated epilepsy. Other cases have been reported with SHROOM4 variants and variable ID, congenital malformations, and CC agenesis - the mechanism of disease is not yet clear. Hence, SHROOM4 is tagged for promotion to Green with a request for expert review, due to confounding evidence of disease association. Addition of SHROOM4 to this panel would ensure inclusion on the R27 Paediatric disorders panel.; to: Comment on list classification: There are more than 3 unrelated individuals with hemizygous SHROOM4 variants (missense and non-canonical splice) and isolated epilepsy. Other cases have been reported with SHROOM4 variants and variable ID, congenital malformations, and CC agenesis - the mechanism of disease is not yet clear. Hence, SHROOM4 is tagged for promotion to Green with a request for expert review, due to confounding evidence of disease association. Addition of SHROOM4 to this panel would ensure inclusion on the R27 Paediatric disorders panel.
Intellectual disability v9.387 RNU2-2P Achchuthan Shanmugasundram Publications for gene: RNU2-2P were set to 40210679; 40442284
Early onset or syndromic epilepsy v8.187 RNU2-2P Achchuthan Shanmugasundram Publications for gene: RNU2-2P were set to 40210679; 40442284; 41912933
Early onset or syndromic epilepsy v8.187 SHROOM4 Ida Ertmanska Classified gene: SHROOM4 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.187 SHROOM4 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 unrelated individuals with hemizygous SHROOM4 variants and isolated epilepsy. Other cases have been reported with SHROOM4 variants and variable ID, congenital malformations, and CC agenesis - the mechanism of disease is not yet clear. Hence, SHROOM4 is tagged for promotion to Green with a request for expert review, due to confounding evidence of disease association. Addition of SHROOM4 to this panel would ensure inclusion on the R27 Paediatric disorders panel.
Early onset or syndromic epilepsy v8.187 SHROOM4 Ida Ertmanska Gene: shroom4 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.186 SHROOM4 Ida Ertmanska gene: SHROOM4 was added
gene: SHROOM4 was added to Early onset or syndromic epilepsy. Sources: Literature
Q2_26_promote_green, Q2_26_expert_review tags were added to gene: SHROOM4.
Mode of inheritance for gene: SHROOM4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SHROOM4 were set to 16249884; 25167861; 26740508; 32565546; 32728808; 35663265; 35937050; 36379543; 40905141
Phenotypes for gene: SHROOM4 were set to epilepsy, MONDO:0005027
Review for gene: SHROOM4 was set to GREEN
Added comment: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36209347 Peduto et al., 2022
Report of a 2yo male with SHROOM4 c.4153C>T, p.Arg1385*, which is also present in an unaffected grandfather. The authors question pathogenicity of SHROOM4 LoF variants (missense GoF still seen as potentially disease causing).

PMID: 35937050 Lee et al., 2022
Cohort of patients with infantile spasms. Sample IS06 - male; trio WGS detected a SHROOM4 NM_020717: c.269+4A>G hemizygous variant - classified as VUS by authors.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Sources: Literature
Intellectual disability v9.386 SHROOM4 Ida Ertmanska changed review comment from: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).; to: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36209347 Peduto et al., 2022
Report of a 2yo male with SHROOM4 c.4153C>T, p.Arg1385*, which is also present in an unaffected grandfather. The authors question pathogenicity of SHROOM4 LoF variants (missense GoF still seen as potentially disease causing).

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Intellectual disability v9.386 SHROOM4 Ida Ertmanska Phenotypes for gene: SHROOM4 were changed from Stocco dos Santos X-linked mental retardation syndrome, 300434; Intellectual disability to neurodevelopmental disorder, MONDO:0700092; X-linked intellectual disability, Stocco dos Santos type, MONDO:0010325
Intellectual disability v9.385 SHROOM4 Ida Ertmanska Publications for gene: SHROOM4 were set to 12673656; 16249884; 26740508; 20613765
Intellectual disability v9.384 SHROOM4 Ida Ertmanska Tag disputed tag was added to gene: SHROOM4.
Intellectual disability v9.384 SHROOM4 Ida Ertmanska edited their review of gene: SHROOM4: Changed publications to: 16249884, 25167861, 26740508, 32565546, 32728808, 35663265, 36379543, 40905141
Intellectual disability v9.384 SHROOM4 Ida Ertmanska commented on gene: SHROOM4: Comment on list classification: The association between SHROOM4 and Intellectual disability has been disputed by ClinGen in 2021, mostly due to reported SHROOM4 variants being too common in gnomAD. Subsequent publications reported SHROOM4 variants as causal in six individuals with epilepsy without ID, two unrelated cases with syndromic congenital malformations without ID / DD, and two fetal cases with CC agenesis. There are 3 unrelated cases reported with ID / DD and insertion or deletion affecting SHROOM4, in addition to other genes. As the effect of disrupting other genes cannot be decoupled, these cases are not taken into account for gene-disease association. Due to limited and conflicting evidence linking SHROOM4 to Intellectual disability, this gene can only be rated Amber for now.
Intellectual disability v9.384 SHROOM4 Ida Ertmanska changed review comment from: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).; to: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).
+Functional studies: Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls.

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Intellectual disability v9.384 SHROOM4 Ida Ertmanska changed review comment from: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and also found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).; to: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and in one case found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Intellectual disability v9.384 SHROOM4 Ida Ertmanska changed review comment from: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and also found in unaffected family members.

Other publications:
PMID: 35663265 Bian et al., 2022

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A p.(Glu314Lys) - 1 affected male and 1 affected hemizygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).; to: The association between SHROOM4 and X-linked complex neurodevelopmental disorder has been classified as Disputed in ClinGen in 2021. ClinGen curation included evaluation of the following sources: PMID: 16249884 Hagens et al., 2006; PMID: 25167861 Redin et al., 2014; PMID: 26740508 Lopes et al., 2016. These cases were not scored as the SHROOM4 variants were too common in gnomAD, and also found in unaffected family members.

Other publications:
PMID: 32565546 Heide et al., 2020
Patient 44 - fetal case, pregnancy terminated - individual hemizygous for SHROOM4 NM_020717.3c.2050C>T, p.(Arg684*), with complete CC agenesis and other malformations: Blake’s pouch cyst, Turner syndrome: mos 46,X, psu idic(X)(p11.2)[19]/45,X[6]. Method: exome seq.

PMID: 32728808 Dong et al., 2021
Individual 31M with a chromosomal insertion affecting SHROOM4, MAGED1, and PFKFB1 - male with moderate dev delay and autism spectrum. Cannot decouple the effect of individual genes being disrupted here.

PMID: 35663265 Bian et al., 2022
Chinese epilepsy cohort. Six hemizygous (maternally inherited) missense SHROOM4 variants detected in six cases with idiopathic epilepsy without intellectual disability: c.13C > A, p. Pro5Thr; c.3236A>C, p.Glu1079Ala; c.3581C > T, p.Ser1194Leu; c.4288C > T, p.Arg1430Cys; c.4303G > A, p.Val1435Met; c.4331C > T, p.Pro1444Leu. Seizure onset at 3-16 years (median 5.5yrs). Brain MRI was normal in 6/6 cases. Note: variants p.Ser1194Leu and p.Arg1430Cys have hemizygous individuals reported in gnomAD 4.1.1.

PMID: 36379543 Kolvenbach et al., 2023
6 individuals from 4 families with SHROOM4 variants and congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems.
Family A: SHROOM4 c.940G>A , p.(Glu314Lys) - 1 affected male and 1 affected heterozygous female with skewed X-inactivation (84% towards the mutated maternal chromosome); shared phenotype: Unilateral renal agenesis, anorectal malformation, and oesophageal atresia with fistula - VATER/VACTERL diagnosis; no DD or ID. Variant present in 4 het female individuals in gnomAF v4.1.1.
Family B: SHROOM4 c.3942+1G>A - affected male, variant was maternally inherited; phenotype: atrial septal defect, unilateral kidney dysplasia, bilateral clinodactyly of the fifth finger, left-sided single palmar crease, pes equinovarus, dysmorphic craniofacial features, gastro-oesophageal reflux, hypotonia and failure to thrive; no DD or ID. Variant not in gnomAD v4.1.1.
Families C & D - microdeletions including CLCN5 and SHROOM4 - DD and intellectual disability noted; affected individuals in both families showed clinical characteristics of Dent’s disease (CLCN5-related).

PMID: 40905141 Héron et al., 2025
Patient 62 - female fetal case with complete CC agenesis and a de novo SHROOM4 variant NM_020717.3:c.2050C>T, p.(Arg684*). Pregnancy was terminated. From suppl info. Possibly same case as in PMID: 32565546 ? Same research group.

SHROOM4 is not associated with any phenotype in OMIM (accessed 21st Apr 2026).
Retinal disorders v8.124 AP5B1 Ida Ertmanska changed review comment from: 2 unrelated cases reported in PMID: 40081374 - see review by Sarah Leigh.

New cases:
PMID: 41830174 Hussian et al., 2026
2 unrelated European families reported with biallelic AP5B1 variants and AP5B1-related retinopathy.
Family 4: female proband, homozygous for AP5B1: c. 2354T>C, p.Leu785Pro. Diagnosed with retinal dystrophy at age 33yrs.
Family 5: female proband, age 44yrs (disease onset at 39yrs), with compound het AP5B1 variants: c. 2354T>C, p.Leu785Pro & c.188delA, p.Gln63Argfs*95.

This gene is not yet associated with a phenotype in OMIM (accessed 15th Apr 2026).; to: 2 unrelated cases reported in PMID: 40081374 - see review by Sarah Leigh.

New cases:
PMID: 41830174 Hussain et al., 2026
2 unrelated European families reported with biallelic AP5B1 variants and AP5B1-related retinopathy.
Family 4: female proband, homozygous for AP5B1: c. 2354T>C, p.Leu785Pro. Diagnosed with retinal dystrophy at age 33yrs.
Family 5: female proband, age 44yrs (disease onset at 39yrs), with compound het AP5B1 variants: c. 2354T>C, p.Leu785Pro & c.188delA, p.Gln63Argfs*95.

This gene is not yet associated with a phenotype in OMIM (accessed 15th Apr 2026).
Intellectual disability v9.384 SHROOM4 Ida Ertmanska reviewed gene: SHROOM4: Rating: AMBER; Mode of pathogenicity: None; Publications: 16249884, 25167861, 26740508, 35663265, 36379543; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska commented on Region: ISCA-37432-Loss: Comment on list classification: 17q12 deletions affecting the gene HNF1B are a well established cause of Renal cysts and diabetes syndrome. Diabetes is often a presenting symptom in affected individuals. ClinGen Haploinsufficiency score is 3, suggesting dosage sensitivity. Hence, region ISCA-37432-Loss should be promoted to Green on Monogenic diabetes. The change is also tagged for expert review, in order to determine if there are any technical limitations that would prevent 17q12 deletions from being detected in this test.
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska reviewed Region: ISCA-37432-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: 28420700, 41809577; Phenotypes: Type 2 diabetes mellitus, OMIM:125853, Renal cysts and diabetes syndrome, OMIM:137920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic diabetes v3.18 HNF1B Ida Ertmanska reviewed gene: HNF1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 28420700, 41809577; Phenotypes: Type 2 diabetes mellitus, OMIM:125853, Renal cysts and diabetes syndrome, OMIM:137920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska Tag Q2_26_promote_green tag was added to Region: ISCA-37432-Loss.
Tag Q2_26_expert_review tag was added to Region: ISCA-37432-Loss.
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska Classified Region: ISCA-37432-Loss as Amber List (moderate evidence)
Monogenic diabetes v3.18 ISCA-37432-Loss Ida Ertmanska Region: isca-37432-loss has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v3.17 ISCA-37432-Loss Ida Ertmanska Tag curated_removed was removed from Region: ISCA-37432-Loss.
Childhood onset hereditary spastic paraplegia v8.51 RNU4-2 Achchuthan Shanmugasundram Classified gene: RNU4-2 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.51 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are over 20 unrelated families reported with biallelic RNU4-2 variants and with a neurodevelopmental disorder, of which spasticity was reported in over 10 families. Spasticity was not reported as one of the presentations of ReNU syndrome (MIM #620851) that is associated with monoallelic RNU4-2 variants. Hence, the MOI should be set as 'BIALLELIC, autosomal or pseudoautosomal' and the gene should be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.51 RNU4-2 Achchuthan Shanmugasundram Gene: rnu4-2 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.50 RNU4-2 Achchuthan Shanmugasundram Phenotypes for gene: RNU4-2 were changed from to neurodevelopmental disorder, MONDO:0700092
Childhood onset hereditary spastic paraplegia v8.49 RNU4-2 Achchuthan Shanmugasundram gene: RNU4-2 was added
gene: RNU4-2 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q2_26_promote_green tags were added to gene: RNU4-2.
Mode of inheritance for gene: RNU4-2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU4-2 were set to 41951737; 41951959
Review for gene: RNU4-2 was set to GREEN
Added comment: PMID:41951737 (2026) reported a saturation genome editing experiment where they simultaneously measured the functional impact of variants across RNU4-2 in a haploid cell line. These data led them to identify a new recessive NDD caused by biallelic variants outside the T-loop and Stem III regions in which heterozygous variants cause ReNU syndrome.

PMID:41951959 (2026) reported a new recessive neurodevelopmental disorder associated with biallelic (both homozygous and compound heterozygous) variants in RNU4-2 gene. There were 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. Detailed phenotypic information was available for 31 patients from 24 unrelated families, which demonstrates that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Spasticity was reported in 14 individuals from 11 families, while movement and coordination abnormalities were observed in 13 of 31 individuals, nine with ataxia, three with dystonia, one with choreoathetosis and one unspecified abnormality of coordination.

Biallelic variants in RNU4-2 gene are not yet associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Early onset or syndromic epilepsy v8.185 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are over 20 unrelated families reported with biallelic RNU4-2 variants and with a neurodevelopmental disorder, of which seizures were reported in over 10 families. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Early onset or syndromic epilepsy v8.185 RNU4-2 Achchuthan Shanmugasundram Mode of inheritance for gene: RNU4-2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v8.184 RNU4-2 Achchuthan Shanmugasundram Publications for gene: RNU4-2 were set to 38821540; 38645094
Early onset or syndromic epilepsy v8.183 RNU4-2 Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: RNU4-2.
Tag Q2_26_NHS_review tag was added to gene: RNU4-2.
Early onset or syndromic epilepsy v8.183 RNU4-2 Achchuthan Shanmugasundram edited their review of gene: RNU4-2: Added comment: PMID:41951737 (2026) reported a saturation genome editing experiment where they simultaneously measured the functional impact of variants across RNU4-2 in a haploid cell line. These data led them to identify a new recessive NDD caused by biallelic variants outside the T-loop and Stem III regions in which heterozygous variants cause ReNU syndrome.

PMID:41951959 (2026) reported a new recessive neurodevelopmental disorder associated with biallelic (both homozygous and compound heterozygous) variants in RNU4-2 gene. There were 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. Detailed phenotypic information was available for 31 patients from 24 unrelated families, which demonstrates that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Seizures were reported in 19 individuals from 13 families.

Biallelic variants in RNU4-2 gene are not yet associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; Changed publications to: 41951737, 41951959; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v9.384 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are over 20 unrelated families reported with biallelic RNU4-2 variants and with a neurodevelopmental disorder comprising GDD/ ID. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Intellectual disability v9.384 RNU4-2 Achchuthan Shanmugasundram Mode of inheritance for gene: RNU4-2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v9.383 RNU4-2 Achchuthan Shanmugasundram Tag Q2_26_NHS_review tag was added to gene: RNU4-2.
Intellectual disability v9.383 RNU4-2 Achchuthan Shanmugasundram Publications for gene: RNU4-2 were set to 38821540; 38645094; 38991538
Intellectual disability v9.382 RNU4-2 Achchuthan Shanmugasundram Tag Q2_26_MOI tag was added to gene: RNU4-2.
Intellectual disability v9.382 RNU4-2 Achchuthan Shanmugasundram edited their review of gene: RNU4-2: Added comment: PMID:41951737 (2026) reported a saturation genome editing experiment where they simultaneously measured the functional impact of variants across RNU4-2 in a haploid cell line. These data led them to identify a new recessive NDD caused by biallelic variants outside the T-loop and Stem III regions in which heterozygous variants cause ReNU syndrome.

PMID:41951959 (2026) reported a new recessive neurodevelopmental disorder associated with biallelic (both homozygous and compound heterozygous) variants in RNU4-2 gene. There were 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. Detailed phenotypic information was available for 31 patients from 24 unrelated families, which demonstrates that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Global developmental delay (GDD) with moderate+ severity was reported in 28 individuals from 22 families and intellectual disability (ID) of moderate+ severity was reported in 24 individuals from 19 families.

Biallelic variants in RNU4-2 gene are not yet associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; Changed publications to: 41951737, 41951959; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v8.124 RNU4-2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with MIM #621560 in OMIM (OMIM record last accessed 20 April 2026).